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	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 252199). 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