# NM_000527.5(LDLR):c.1027G>A (p.Gly343Ser)

https://sugi.bio/variant/ldlr-p-gly343ser

## Summary

**LDLR p.Gly343Ser (c.1027G>A)** is classified **Pathogenic** in LDLR (ClinVar, Expert panel, 48 submitters; last evaluated 2023-04-28). AlphaMissense: ambiguous (0.3914); Very rare (popmax 0.00834%, amr); Associated with hypercholesterolemia, familial, 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs730882096 · 48 submitters · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered disease-causing, submitted by 48 submitters, and is linked to hypercholesterolemia, familial, 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Clinical trials | 28 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024574/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [LDLR](https://sugi.bio/atlas/gene/LDLR/) |
| Protein change (HGVS p.) | p.Gly343Ser |
| Coding change (HGVS c.) | c.1027G>A |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs730882096](https://www.ncbi.nlm.nih.gov/snp/rs730882096/) |
| Variant type | single nucleotide variant |
| Location | chr19:11110738-11110738 (GRCh38) |
| ClinVar | [VCV183106](https://www.ncbi.nlm.nih.gov/clinvar/variation/183106/) |

**All HGVS expressions:** `LRG_274:g.26358G>A`, `LRG_274t1:c.1027G>A`, `NC_000019.10:g.11110738G>A`, `NC_000019.9:g.11221414G>A`, `NG_009060.1:g.26358G>A`, `NM_000527.2:c.1027G>A`, `NM_000527.5:c.1027G>A`, `NM_001195798.2:c.1027G>A`, `NM_001195799.2:c.904G>A`, `NM_001195800.2:c.523G>A`, `NM_001195803.2:c.646G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.3914) — no call either way
- REVEL 0.929 (moderately pathogenic-leaning)
- SaProt LLR -11.644 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 11.75, GERP 1.39, phastCons 1 — highly conserved
- CADD: **PHRED 29.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.00** across the covering region of the MANE Select transcript (11,089,549–11,131,313), spanning 41,764 bp. Chi-square p 0.91. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.0026% · 5/59,974 in the highest group · 55/1,613,638 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,995 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,825 |
| European (non-Finnish) | 0.00381% | 26,222 |
| East Asian | 0.00223% | 44,890 |
| South Asian | 0.0011% | 91,086 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**LDLR** population constraint: LOEUF 1.091, pLI 1.2477e-30, missense-Z 0.60522; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hypercholesterolemia, familial, 1** — Definitive (SD)

## Protein context {#protein}

Residue **343** lies in the egf-like 1 domain; a UniProt-annotated variant site (in fhcl1; pathogenic; picardie); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 75.81, 29% of residues very-high.

**36 experimental structure(s)** (PDB): [1AJJ](https://www.rcsb.org/structure/1AJJ), [1D2J](https://www.rcsb.org/structure/1D2J), [1F5Y](https://www.rcsb.org/structure/1F5Y), [1F8Z](https://www.rcsb.org/structure/1F8Z), [1HJ7](https://www.rcsb.org/structure/1HJ7), [1HZ8](https://www.rcsb.org/structure/1HZ8) — incl. mutant structure 2W2N.

## What this gene does {#gene-function}

*Describes the biological roles of LDLR (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** LDLR's established molecular role includes protease binding. p.Gly343Ser falls in the egf-like 1 domain.


### Pathways affected {#pathways}

LDLR participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cargo recognition for clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856825) | curated |
| [Clathrin-mediated endocytosis](https://reactome.org/content/detail/R-HSA-8856828) | curated |
| [LDL clearance](https://reactome.org/content/detail/R-HSA-8964038) | curated |
| [Chylomicron clearance](https://reactome.org/content/detail/R-HSA-8964026) | electronic |
| [Retinoid metabolism and transport](https://reactome.org/content/detail/R-HSA-975634) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, low-density lipoprotein particle receptor activity, low-density lipoprotein particle binding, very-low-density lipoprotein particle receptor activity, identical protein binding, molecular adaptor activity.

**Biological process:** negative regulation of receptor recycling, long-term memory, negative regulation of low-density lipoprotein particle clearance, intestinal cholesterol absorption, cholesterol transport, low-density lipoprotein particle clearance.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-04-28.

**Submitter consensus:** conflicting (33 Pathogenic, 8 Likely pathogenic, 5 Uncertain significance, 1 pathogenic, 1 not provided).

**Submission history:** 39 submissions (2016–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Familial Hypercholesterolemia VCEP (hypercholesterolemia, familial). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2`, `PP1_Strong`, `PS3`, `PS4`, `PP3`, `PP4`, `PM3`, `BS4`, `PM5`.
Inheritance: Semidominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_000527.5 (LDLR):c.1027G>A (p.Gly343Ser) variant is classified as Pathogenic (modified) for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3, PS3, PP4, PS4, PP1_Strong, PM5, PM3, BS4) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012).  The supporting evidence is as follows: PM2: PopMaxMAF=0.00005 in East Asian population from gnomAD (gnomAD v2.1.1). PP3: REVEL=0.929, it is above 0.75. PS3: Level 1 assays: PMID 15100232. Heterologous cells (CHO) were used in WB, FACS and NMR Spectroscopy. The experiments shown <60% cell surface LDLR expression (Fig 5C), and >80% expressed receptor bind and release LDL upon low pH condition (Fig 6B), the amount of LDL bound to the mutant receptor correlates tightly with cell-surface LDLR expression, NMR indicates misfolding defects of the receptor. Functional data is consistent with damaging effect. This study is reported by Boswell et al, 2004, from Department of Biochemistry, Division of Structural Biology, University of Oxford, UK.  PP4: Variant meets PM2 and is identified in at least ˃1 index cases who fulfil criteria for FH after alternative causes of high cholesterol were excluded. PS4: Variant meets PM2 and is identified in at least 26 index cases reported in VCI and PubMed. There are 14 unrelated index case reported in VCI who fulfil criteria for FH diagnosis: Twelve cases fulfil DLCN criteria, 7 reported from Service de Biochimie et de Biologie Moléculaire, Hospices Civils de Lyon, Lyon, France, 1 from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 2 from Research Lab of Molecular Genetics of Lipid Metabolism; and 2 from Robarts Research Institute, Canada; two cases fulfil Simon Broome possible criteria, reported from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge. Variant is reported in PubMed in at least 12 index cases fulfil criteria for FH diagnosis: 8 cases fulfil DLCN probable/definite FH criteria in PMID 11040093, 11810272, 32977124, 30270055, 27784735; 1 case fulfil Simon Broome possible FH criteria in PMID 26748104; 3 cases fulfil MedPed criteria in PMID 8882879, 27824480.  PP1_Strong: Variant segregates with FH phenotype in 18 informative meiosis from 6 families reported from 4 different labs in VCI: 11 affected carries and 7 unaffected non-carriers reported from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism.  PM5: Three other variants at the same codon: NM_000527.5(LDLR):c.1028G>T (p.Gly343Val)(ClinVarID 440618) classified as Likely Pathogenic, NM_000527.5(LDLR):c.1028G>A (p.Gly343Asp)(ClinVarID 251606) is classified as Likely Pathogenic,  NM_000527.5(LDLR):c.1027G>T (p.Gly343Cys)(ClinVarID 251605) is classified as Pathogenic, by these guidelines, therefore PM5 is met. PM3: Variant meets PM2 and is identified in an index case with homozygous FH phenotype (untreated LDL-C > 500mg/dL, or LDL-C > 300 mmol/dL on high-intensive lipid-lowering therapy and the presence of tendon xanthomas before 10 year of age), reported by Sanchez-Hernandez et al, 2016, Universitario Insular Materno Infantil de Gran Canaria, Spain, PMID 27784735. This variant met enough pathogenic criteria toward Pathogenic classification by these guidelines before PM3 code applied. BS4: Variant does not segregate with FH phenotype in total of 6 informative meiosis reported in VCI. Five affected relatives without the variant and had LDL-C>75th percentile, 2 cases from Cardiovascular Genetics Laboratory (PathWest Laboratory Medicine WA), 1 case each from Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge, Laboratory of Genetics and Molecular Cardiology, and Research Lab of Molecular Genetics of Lipid Metabolism. There is 1 instance reported from 1 laboratory, where an unaffected family member had LDL-C<50th percentile and carries the variant, reported in VCI from Laboratory of Genetics and Molecular Cardiology, GTR LabID 505581.  Variant has 3 Strong, 3 Moderate and 2 Supporting evidence codes toward Pathogenic, enough to classify as Pathogenic, and only 1 Strong evidence code towards Benign. The Pathogenic criteria overwhelms the Benign criteria, so we are confident in classifying this variant as Pathogenic.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50004 · approved 2023-04-28 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/2fc03ee7-785f-44c9-bac0-10c93ad52227).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-28 |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-05-09 |
| All of Us Research Program, National Institutes of Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-09 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | pathogenic | criteria provided, single submitter | clinical testing | 2023-10-16 |
| U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille | Pathogenic | criteria provided, single submitter | clinical testing | 2017-03-30 |
| Dept. of Genetics and Pharmacogenomics, Merck Research Labs | not provided | no classification provided | in vitro |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-12 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-29 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-20 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-01 |
| Robarts Research Institute, Western University | Likely pathogenic | criteria provided, single submitter | clinical testing |  |
| Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix | Likely pathogenic | criteria provided, single submitter | clinical testing | 2016-12-16 |
| Laboratory of Genetics and Molecular Cardiology, University of São Paulo | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | Pathogenic | no assertion criteria provided | research |  |
| Fundacion Hipercolesterolemia Familiar | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Iberoamerican FH Network | Uncertain significance | criteria provided, single submitter | research | 2016-03-01 |
| Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2019-08-02 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2020-05-28 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Likely pathogenic | no assertion criteria provided | clinical testing |  |
| AiLife Diagnostics, AiLife Diagnostics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-02-25 |
| Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Pathogenic | no assertion criteria provided | clinical testing | 2023-11-24 |
| Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham | Likely pathogenic | no assertion criteria provided | clinical testing | 2023-01-01 |
| Genome-Nilou Lab | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-05-18 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-10 |
| Revvity Omics, Revvity | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-11-11 |
| LIPIGEN - Lipid Transport Disorders Italian Genetic Network | Pathogenic | criteria provided, single submitter | research | 2025-01-01 |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Pathogenic | criteria provided, single submitter | clinical testing |  |
| Natera, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-09 |
| LDLR-LOVD, British Heart Foundation | Likely pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-05-24 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Pathogenic | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Pathogenic | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-17 |
| ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2023-04-28 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-06-17 |
| Laboratory of Molecular Genetics, National Medical Research Center for Therapy and Preventive Medicine | Uncertain significance | criteria provided, single submitter | research |  |
| MGZ Medical Genetics Center | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-18 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2024-01-30 |
| Department of Traditional Chinese Medicine, Fujian Provincial Hospital | Pathogenic | no assertion criteria provided | research |  |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-19 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2025-07-25 |
| Dasa | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-06 |
| 3billion | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-17 |
| Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2024-07-23 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-30 |
| Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Pathogenic | criteria provided, single submitter | clinical testing | 2026-09-02 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-11-01 |

## Associated conditions {#conditions}

[hypercholesterolemia, familial, 1](https://sugi.bio/atlas/disease/hypercholesterolemia-familial-1/), [familial hypercholesterolemia](https://sugi.bio/atlas/disease/familial-hypercholesterolemia/), [homozygous familial hypercholesterolemia](https://sugi.bio/atlas/disease/homozygous-familial-hypercholesterolemia/).

**Reported phenotype names (ClinVar):** Hypercholesterolemia, familial, 1, not provided, Familial hypercholesterolemia, Homozygous familial hypercholesterolemia, Cardiovascular phenotype, LDLR-related disorder, LDLR-related condition, Familial hypercholesterolemias, Familial hypercholesterolaemia, none provided.

## Same-residue context {#hotspot}

Residue **343** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Gly343Cys](/variant/ldlr-p-gly343cys), [LDLR p.Gly343Asp](/variant/ldlr-p-gly343asp), [LDLR p.Gly343Ala](/variant/ldlr-p-gly343ala), [LDLR p.Gly343Val](/variant/ldlr-p-gly343val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Gly343Asp](/variant/ldlr-p-gly343asp), [LDLR p.Gly343Cys](/variant/ldlr-p-gly343cys), [LDLR p.Gly343Val](/variant/ldlr-p-gly343val), [LDLR p.Gly343Ala](/variant/ldlr-p-gly343ala), [LDLR p.Gly343=](/variant/ldlr-p-gly343), [LDLR c.1186+5G>A](/variant/ldlr-c-1186-plus-5g-a), [LDLR c.1359-1G>A](/variant/ldlr-c-1359-minus-1g-a), [LDLR c.1359-5C>G](/variant/ldlr-c-1359-minus-5c-g).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 183106). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*