Submissions for variant NM_000527.5(LDLR):c.693C>A (p.Cys231Ter)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000003928	SCV000294914	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000003928	SCV000484681	likely pathogenic	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000003928	SCV000503223	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 9 with co-segregation
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000003928	SCV000540756	pathogenic	Hypercholesterolemia, familial, 1	2016-11-05	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000003928	SCV000583728	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000003928	SCV000588513	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Color Diagnostics, LLC DBA Color Health	RCV000775046	SCV000909144	pathogenic	Familial hypercholesterolemia	2018-06-18	criteria provided, single submitter	clinical testing	Pathogenic variant based on current evidence: This variant is a single nucleotide substitution in exon 4 of the LDLR gene, which creates a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. While this variant is rare in the general population (0/277264 chromosomes in the Genome Aggregation Database (gnomAD)), it has been reported in multiple individuals affected with familial hypercholesterolemia (PMID: 8093663, 16389549, 22883975). Truncating variants in LDLR are known to be pathogenic (PMID: 20809525). Based on available evidence, this variant is classified as Pathogenic.
Invitae	RCV000775046	SCV000952013	pathogenic	Familial hypercholesterolemia	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys231*) 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 individuals with familial hypercholesterolemia (PMID: 8093663, 10559517, 16389549, 20145306, 21310417, 22698793, 22883975, 27680772). This variant is also known as Cys210X. ClinVar contains an entry for this variant (Variation ID: 3730). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002362558	SCV002664339	pathogenic	Cardiovascular phenotype	2022-09-08	criteria provided, single submitter	clinical testing	The p.C231* pathogenic mutation (also known as c.693C>A), located in coding exon 4 of the LDLR gene, results from a C to A substitution at nucleotide position 693. This changes the amino acid from a cysteine to a stop codon within coding exon 4. This alteration (also described as p.C210*) has been reported in familial hypercholesterolemia cohorts (Gudnason V et al. Arterioscler. Thromb., 1993 Jan;13:56-63; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Dušková L et al. Atherosclerosis, 2011 May;216:139-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
OMIM	RCV000003928	SCV000024093	pathogenic	Hypercholesterolemia, familial, 1	1993-01-01	no assertion criteria provided	literature only
Cardiovascular Genetics Laboratory, PathWest Laboratory Medicine WA - Fiona Stanley Hospital	RCV000003928	SCV000268583	pathogenic	Hypercholesterolemia, familial, 1	2008-07-09	no assertion criteria provided	clinical testing
deCODE genetics, Amgen	RCV000003928	SCV004022251	pathogenic	Hypercholesterolemia, familial, 1	2023-07-21	no assertion criteria provided	research	The variant NM_000527.5:c.693C>A (chr19:11105599) in LDLR was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). Following imputation in a set of 166K Icelanders (4 imputed heterozygotes) we observed an association with LDL cholesterol using measurements from 128289 individuals (Effect (SD)= 3.59, P= 4.14e-10) and Non-HDL cholesterol using measurements from 136901 individuals (Effect (SD)= 3.26, P= 1.50e-08). This variant has been reported in ClinVar previously as pathogenic/likely pathogenic. Based on ACMG criteria (PVS1, PS4, PM2 ) this variant classifies as pathogenic.