Variant: NM_000527.5(LDLR):c.1329G>T (p.Trp443Cys)

CA10585410

251793 (ClinVar)

Gene: LDLR

Condition: hypercholesterolemia, familial

Inheritance Mode: Semidominant inheritance

UUID: b56be71f-abe1-4414-b266-91bc2874bbb0

Approved on: 2025-01-31

Published on: 2025-02-03

HGVS expressions

NM_000527.5:c.1329G>T
NM_000527.5(LDLR):c.1329G>T (p.Trp443Cys)
NC_000019.10:g.11113420G>T
CM000681.2:g.11113420G>T
NC_000019.9:g.11224096G>T
CM000681.1:g.11224096G>T
NC_000019.8:g.11085096G>T
NG_009060.1:g.29040G>T
ENST00000252444.10:c.1587G>T
ENST00000559340.2:c.1329G>T
ENST00000560467.2:c.1209G>T
ENST00000558518.6:c.1329G>T
ENST00000252444.9:c.1583G>T
ENST00000455727.6:c.825G>T
ENST00000535915.5:c.1206G>T
ENST00000545707.5:c.948G>T
ENST00000557933.5:c.1329G>T
ENST00000558013.5:c.1329G>T
ENST00000558518.5:c.1329G>T
ENST00000559340.1:c.50G>T
ENST00000560173.1:n.328G>T
ENST00000560467.1:c.809G>T
NM_000527.4:c.1329G>T
NM_001195798.1:c.1329G>T
NM_001195799.1:c.1206G>T
NM_001195800.1:c.825G>T
NM_001195803.1:c.948G>T
NM_001195798.2:c.1329G>T
NM_001195799.2:c.1206G>T
NM_001195800.2:c.825G>T
NM_001195803.2:c.948G>T

Likely Pathogenic

• Met criteria codes: PS1 PP4 PP3 PM2 PS4_Supporting

Expert Panel

Familial Hypercholesterolemia VCEP

Criteria Specification Information

Criteria Specification: ClinGen Familial Hypercholesterolemia Expert Panel Specifications to the ACMG/AMP Variant Classification Guidelines Version 1.2

Evidence submitted by expert panel

Familial Hypercholesterolemia VCEP

The NM_000527.5(LDLR):c.1329G>T (p.Trp443Cys) variant is classified as Likely Pathogenic for Familial Hypercholesterolemia by applying ACMG/AMP evidence codes PS1, PM2, PP3, PP4 and PS4_Supporting as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (specification version 1.2) on 31 January 2025. The supporting evidence is as follows: PM2: PopMax MAF = 0.0000006841 (0.00006841%) in European (non-Finnish) exomes (gnomAD v4.1.0). PP3: REVEL = 0.961. PS1: 1 missense variant that leads to the same amino acid change - NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant (ClinVar ID 251792), classified as Pathogenic by these guidelines. PS4_Supporting, PP4: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN score >=6 (2 cases from Robarts Research Institute, Canada; 1 case from PMID 11810272- Fouchier et al., 2001, The Netherlands).

Met criteria codes

• PS1: 1 more missense variant that leads to the same amino acid change: - NM_000527.5(LDLR):c.1329G>C (p.Trp443Cys) variant (ClinVar ID 251792) - classified as Pathogenic by these guidelines
• PP4: Variant meets PM2 and is identified in at least 1 index case who fulfills DLCN>=6 criteria for FH (Robarts Research Institute) after alternative causes of high cholesterol were excluded.
• PP3: REVEL = 0.961
• PM2: PopMax MAF = 0.0000006841 (0.00006841%) in European (non-Finnish) exomes (gnomAD v4.1.0).
• PS4_Supporting: Variant meets PM2 and is identified in at least 3 unrelated index cases who fulfill DLCN>=6 criteria for FH: (1): Robarts Research Institute- 2 FH patients with DLCN >=6 carry variant (2): PMID: 11810272- 1 FH patients with DLCN >=6 carry variant