Submissions for variant NM_000527.5(LDLR):c.2056C>T (p.Gln686Ter)

dbSNP: rs879255126

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237466	SCV000295850	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge	RCV000237466	SCV000322998	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research	0/200 non-FH alleles
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000237466	SCV000503455	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 / previously described in association with FH
Ambry Genetics	RCV002418067	SCV002725561	pathogenic	Cardiovascular phenotype	2020-10-14	criteria provided, single submitter	clinical testing	The p.Q686* pathogenic mutation (also known as c.2056C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2056. This changes the amino acid from a glutamine to a stop codon within coding exon 14. This mutation (also known as legacy p.Q665*) has been reported in individuals with familial hypercholesterolemia from multiple ethnic backgrounds (Thiart R et al. Mol Cell Probes, 1997 Dec;11:457-8; Górski B et al. Hum Genet, 1998 May;102:562-5; Bourbon M et al. Atherosclerosis, 2008 Feb;196:633-42). 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	RCV002518494	SCV003300793	pathogenic	Familial hypercholesterolemia	2022-05-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 252199). For these reasons, this variant has been classified as Pathogenic. This variant is also known as Q665X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 9654205). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln686*) 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).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000237466	SCV005368162	pathogenic	Hypercholesterolemia, familial, 1	2024-05-15	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PS4_MOD,PM2_SUP
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237466	SCV000606589	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research