# NM_000527.5(LDLR):c.369_370del (p.Arg124fs)

https://sugi.bio/variant/ldlr-p-arg124fs

## Summary

**LDLR p.Arg124fs (c.369_370del)** is classified **Pathogenic** in LDLR (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-01). No gnomAD frequency available for this variant; Associated with familial hypercholesterolemia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs879254496 · 5 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the LDLR gene that is considered disease-causing, submitted by 5 submitters, and is linked to familial hypercholesterolemia.

*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 | 111 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [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.Arg124fs |
| Coding change (HGVS c.) | c.369_370del |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs879254496](https://www.ncbi.nlm.nih.gov/snp/rs879254496/) |
| Variant type | Microsatellite |
| Location | chr19:11105271-11105272 (GRCh38) |
| ClinVar | [VCV251182](https://www.ncbi.nlm.nih.gov/clinvar/variation/251182/) |

**All HGVS expressions:** `LRG_274:g.20891TC[2]`, `NC_000019.10:g.11105271TC[2]`, `NC_000019.9:g.11215947TC[2]`, `NG_009060.1:g.20891TC[2]`, `NG_009060.1:g.20895_20896del`, `NM_000527.4:c.369_370delTC`, `NM_000527.5:c.369_370del`, `NM_001195798.2:c.369_370del`, `NM_001195799.2:c.246_247del`, `NM_001195800.2:c.314-2121TC[2]`, `NM_001195803.2:c.314-1294TC[2]`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.48, GERP -2.39, phastCons 0.998 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 18**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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, triplosensitivity 0 (0–3 scale). *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 **124** lies in an α-helix; a disulfide bond; the ldl-receptor class a 3 domain.

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.Arg124fs falls in the ldl-receptor class a 3 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-01.

**Submitter consensus:** unanimous (5/5 Pathogenic).

**Submission history:** 5 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| LDLR-LOVD, British Heart Foundation | Pathogenic | criteria provided, single submitter | literature only | 2016-03-25 |
| Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge | Pathogenic | criteria provided, single submitter | research | 2016-03-01 |
| Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation | Pathogenic | criteria provided, single submitter | clinical testing | 2016-11-05 |
| Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | Pathogenic | criteria provided, single submitter | clinical testing | 2021-05-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial hypercholesterolemia, Hypercholesterolemia, familial, 1, Familial hypercholesterolemias, Familial hypercholesterolaemia, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA, HYPERCHOLESTEROLEMIC XANTHOMATOSIS, FAMILIAL, Fredrickson type IIa hyperlipoproteinemia, Hyperlipoproteinemia type 2.

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg124delinsAlaThrMetGlySerAlaSerLeuProArgTrpGluVal](/variant/ldlr-p-arg124delinsalathrmetglyseralaserleuproargtrpgluval), [LDLR p.Arg124Pro](/variant/ldlr-p-arg124pro), [LDLR p.Arg124Trp](/variant/ldlr-p-arg124trp), [LDLR p.Arg124Gly](/variant/ldlr-p-arg124gly), [LDLR p.Gly219del](/variant/ldlr-p-gly219del), [LDLR p.Phe403del](/variant/ldlr-p-phe403del), [LDLR c.190+2_190+3del](/variant/ldlr-c-190-plus-2-190-plus-3del), [LDLR p.Arg458fs](/variant/ldlr-p-arg458fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 251182). 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.*