Submissions for variant NM_000527.5(LDLR):c.1329G>T (p.Trp443Cys)

dbSNP: rs879254867

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel	RCV000238274	SCV005688690	likely pathogenic	Hypercholesterolemia, familial, 1	2025-01-31	reviewed by expert panel	curation	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).
LDLR-LOVD, British Heart Foundation	RCV000238274	SCV000295372	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000238274	SCV000484760	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857827	SCV002174157	pathogenic	Familial hypercholesterolemia	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 443 of the LDLR protein (p.Trp443Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9727746, 11196104, 22390909). This variant is also known as p.Trp422Cys. ClinVar contains an entry for this variant (Variation ID: 251793). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238274	SCV000606397	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000238274	SCV000733820	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699172	SCV001922787	pathogenic	not provided		no assertion criteria provided	clinical testing