Submissions for variant NM_000527.5(LDLR):c.1998G>A (p.Trp666Ter)

dbSNP: rs752935814

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237406	SCV000295807	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000237406	SCV000540850	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000237406	SCV000583917	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002418060	SCV002720063	pathogenic	Cardiovascular phenotype	2017-10-20	criteria provided, single submitter	clinical testing	The p.W666* pathogenic mutation (also known as c.1998G>A), located in coding exon 14 of the LDLR gene, results from a G to A substitution at nucleotide position 1998. This changes the amino acid from a tryptophan to a stop codon within coding exon 14. This alteration, also referred to as p.W645*, has been reported in individuals with hypercholesterolemia (Kuhrová V et al. Hum. Mutat., 2002 Jan;19:80; Humphries SE et al. J. Mol. Med., 2006 Mar;84:203-14; Marduel M et al. Hum. Mutat., 2010 Nov;31:E1811-24). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002518492	SCV003443168	pathogenic	Familial hypercholesterolemia	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp666*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525, 28645073). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 11754108, 33418990). This variant is also known as W645X. ClinVar contains an entry for this variant (Variation ID: 252161). For these reasons, this variant has been classified as Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV004808651	SCV005434069	pathogenic	not provided	2024-11-01	criteria provided, single submitter	clinical testing	LDLR: PVS1, PM2, PS4:Moderate
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237406	SCV000606572	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research