Submissions for variant NM_000527.5(LDLR):c.1916T>A (p.Val639Asp)

dbSNP: rs794728584

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000238444	SCV000295752	uncertain significance	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	RCV000238444	SCV000503432	likely pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subject mutated among 2600 FH index cases screened = 1/software prediction damaging
Iberoamerican FH Network	RCV000238444	SCV000748103	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Institute of Human Genetics, University of Leipzig Medical Center	RCV000238444	SCV001428876	uncertain significance	Hypercholesterolemia, familial, 1	2018-07-23	criteria provided, single submitter	clinical testing
Invitae	RCV001852309	SCV002299906	pathogenic	Familial hypercholesterolemia	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 639 of the LDLR protein (p.Val639Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 11462246, 16250003, 28502510, 32770674; Invitae). This variant is also known as V618D. ClinVar contains an entry for this variant (Variation ID: 200922). 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 with a positive predictive value of 95%. This variant disrupts the p.Val639 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 22311046), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV002054165	SCV002498420	uncertain significance	not provided	2022-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002408795	SCV002721387	likely pathogenic	Cardiovascular phenotype	2023-09-12	criteria provided, single submitter	clinical testing	The p.V639D variant (also known as c.1916T>A), located in coding exon 13 of the LDLR gene, results from a T to A substitution at nucleotide position 1916. The valine at codon 639 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This variant (also described as legacy p.V618D) has been reported in familial hypercholesterolemia (FH) cohorts, and has been detected in both heterozygous and homozygous FH cases (Nauck MS et al. Hum Mutat. 2001;18(2):165-6; Sánchez-Hernández RM et al. Circ Cardiovasc Genet, 2016 Dec;9:504-510; Bañares VG et al. J Clin Lipidol 2017 Mar;11:524-531; Rutkowska L et al. Genes (Basel), 2022 Jun;13:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly 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 alteration is likely to be pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000238444	SCV000606556	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research