# NM_000527.5(LDLR):c.1784_1790del (p.Arg595fs)

https://sugi.bio/variant/ldlr-p-arg595fs

## Summary

**LDLR p.Arg595fs (c.1784_1790del)** is classified **Pathogenic** in LDLR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2023-12-18). Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs879255020 · 6 submitters · 3 linked conditions · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the LDLR gene that is considered disease-causing, submitted by 6 submitters, and is linked to Cardiovascular phenotype.

*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.*

**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.Arg595fs |
| Coding change (HGVS c.) | c.1784_1790del |
| MANE Select transcript | [NM_000527](https://www.ncbi.nlm.nih.gov/nuccore/NM_000527) |
| dbSNP | [rs879255020](https://www.ncbi.nlm.nih.gov/snp/rs879255020/) |
| Variant type | Deletion |
| Location | chr19:11116936-11116942 (GRCh38) |
| ClinVar | [VCV252028](https://www.ncbi.nlm.nih.gov/clinvar/variation/252028/) |

**All HGVS expressions:** `LRG_274:g.32557_32563del`, `LRG_274t1:c.1784_1790del`, `NC_000019.10:g.11116937_11116943del`, `NC_000019.9:g.11227613_11227619del`, `NG_009060.1:g.32557_32563del`, `NM_000527.4:c.1784_1790delGGAAGAC`, `NM_000527.5:c.1784_1790del`, `NM_000527.5:c.1784_1790delGGAAGAC`, `NM_001195798.2:c.1784_1790del`, `NM_001195799.2:c.1661_1667del`, `NM_001195800.2:c.1280_1286del`, `NM_001195803.2:c.1403_1409del`

## 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 0.041, GERP -1.39, phastCons 0.875 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 12 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 deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,992 in the highest group · 2/1,461,858 alleles overall — very rare (popmax 0.000169%, nfe).

*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 **595** lies in a UniProt-annotated variant site (in fhcl1; pathogenic).

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.


### 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 2023-12-18.

**Submitter consensus:** unanimous (6/6 Pathogenic).

**Submission history:** 6 submissions (2016–2023); 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 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2020-11-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-18 |
| Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital | Pathogenic | no assertion criteria provided | clinical testing | 2023-09-11 |
| Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-01 |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, Hypercholesterolemia, familial, 1, Familial hypercholesterolemia, not provided, Familial hypercholesterolemias, Familial hypercholesterolaemia, none provided, LDL RECEPTOR DISORDER, Hyperlipoproteinemia Type IIa, HYPER-LOW-DENSITY-LIPOPROTEINEMIA.

## Same-residue context {#hotspot}

Residue **595** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [LDLR p.Arg595Trp](/variant/ldlr-p-arg595trp), [LDLR p.Arg595Gln](/variant/ldlr-p-arg595gln), [LDLR p.Arg595Leu](/variant/ldlr-p-arg595leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related LDLR variant pages (same residue, condition, or type): [LDLR p.Arg595Gln](/variant/ldlr-p-arg595gln), [LDLR p.Arg595Leu](/variant/ldlr-p-arg595leu), [LDLR p.Arg595Trp](/variant/ldlr-p-arg595trp), [LDLR p.Arg595=](/variant/ldlr-p-arg595), [LDLR p.Ala612fs](/variant/ldlr-p-ala612fs), [LDLR p.Lys816fs](/variant/ldlr-p-lys816fs), [LDLR p.Tyr400_Phe402del](/variant/ldlr-p-tyr400-phe402del), [LDLR p.Val800fs](/variant/ldlr-p-val800fs).

### 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 2026-10-14); 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 252028). 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.*