Submissions for variant NM_000527.5(LDLR):c.28T>C (p.Trp10Arg)

dbSNP: rs879254386

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237793	SCV000294417	likely pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237793	SCV000503092	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1, family members =2 with co-segregation / software predictions: conflicting
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237793	SCV000583623	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing	ACMG Guidelines: Likely Pathogenic (ii)
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000237793	SCV000588480	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Ambry Genetics	RCV002436068	SCV002751844	likely pathogenic	Cardiovascular phenotype	2019-04-30	criteria provided, single submitter	clinical testing	The p.W10R variant (also known as c.28T>C), located in coding exon 1 of the LDLR gene, results from a T to C substitution at nucleotide position 28. The tryptophan at codon 10 is replaced by arginine, an amino acid with dissimilar properties. This variant has been described in familial hypercholesterolemia (FH) cohorts, although clinical details were limited (Fouchier SW et al. Hum. Mutat., 2005 Dec;26:550-6; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7). An alternate nucleotide change at this position, p.W10R c.28T>A, was reported to be de novo in a pediatric FH case, and functional activity in skin fibroblasts showed reduced LDLR activity (Cassanelli S et al. Clin. Genet., 1998 May;53:391-5). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005090198	SCV005837000	pathogenic	Familial hypercholesterolemia	2024-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 10 of the LDLR protein (p.Trp10Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 9660059, 16250003, 25461735; internal data). In at least one individual the variant was observed to be de novo. This variant is also known as W12R. ClinVar contains an entry for this variant (Variation ID: 250976). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt LDLR protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237793	SCV000605997	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000237793	SCV000733809	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001699170	SCV001920172	likely pathogenic	not provided		no assertion criteria provided	clinical testing