LDLR p.Ser99Ter
c.296C>G · rs377271627 · VCV161269
ClinGen expert panel — Familial Hypercholesterolemia VCEP
Pathogenic for hypercholesterolemia, familial. Applied ACMG criteria (verbatim):
PM2 PVS1 PS3_Supporting PS4 PP4
Curation rationale (ClinGen, verbatim)
The NM_000527.5(LDLR):c.296C>G (p.Ser99Ter) variant is classified as Pathogenic for Familial Hypercholesterolemia by applying evidence codes (PVS1, PS4, PM2, PP4 and PS3_Supporting) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PVS1 - Variant is nonsense, causing a stop at codon 99. It is upstream of amino acid 830, so PVS1 is Met. PS4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PM2 - PopMax MAF = 0.000008791 (0.0009%) in european non-finnish exomes (gnomAD v2.1.1). PP4 - Variant meets PM2. Identified in over 20 unrelated clinical FH cases (PMID: 7718019). PS3_supporting - Level 3 assays: PMID 19148831: Epstein-Barr virus transformed lymphocytes from htz patients, FACS and RNA assays - results - ~60% gene expression, LDL-LDLR uptake and protein at cell surface ---- results are below 85% of wild-type, so PS3_supporting is Met
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | nonsense (stop-gain) | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 3 of 18 |
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 3.2 | GERP -2.3, phastCons 0.99 |
| Overall | ||
| CADD | 34.0 | PHRED · no single calibrated threshold — expert panels disagree |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- LDLR
- Protein
- p.Ser99Ter
- Coding
- c.296C>G
- MANE Select
- NM_000527
- dbSNP
- rs377271627
- Type
- single nucleotide variant
- Location
- chr19:11102769 (GRCh38)
- Gene constraint
- LOEUF 1.091 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 75.81 · 36 PDB
- Residue 99
- an α-helix; the ldl-receptor class a 2 domain
Similar variants
- LDLR c.1186+5G>A Likely pathogenic ★★★ same condition
- LDLR c.1359-1G>A Pathogenic ★★★ same condition
- LDLR c.1359-5C>G Likely pathogenic ★★★ same condition
- LDLR c.1705+2T>C Likely pathogenic ★★★ same condition
- LDLR c.190+4A>T Likely pathogenic ★★★ same condition
- LDLR c.2140+1G>A Pathogenic ★★★ same condition
- LDLR c.2389+2T>G Pathogenic ★★★ same condition
- LDLR c.313+1G>A Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ldlr-p-ser99ter (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown