Submissions for variant NM_000527.5(LDLR):c.11G>A (p.Trp4Ter)

dbSNP: rs201016593

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
LDLR-LOVD, British Heart Foundation	RCV000237276	SCV000294413	pathogenic	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	RCV000237276	SCV000503091	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 2 , family members =4 with co-segregation / FH-Nianjing
Fundacion Hipercolesterolemia Familiar	RCV000237276	SCV000607402	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Iberoamerican FH Network	RCV000237276	SCV000748034	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Invitae	RCV001221497	SCV001393546	pathogenic	Familial hypercholesterolemia	2023-05-26	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: 250973). This variant is also known as FH-Columbia-1 and W18X. This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 1301956, 11668640). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Trp4*) 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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284638	SCV001470526	pathogenic	not provided	2020-08-27	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of LDLR protein synthesis. It has been reported in multiple individuals with Familial hypercholesterolemia in the published literature (PMID: 30270082 (2018), 16314194 (2006), 11668640 (2001), 10206683 (1998), 1301956 (1992)). Therefore, the variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001221497	SCV001983508	pathogenic	Familial hypercholesterolemia	2021-09-23	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.11G>A (p.Trp4X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 248676 control chromosomes. c.11G>A has been widely reported in the literature in individuals affected with Autosomal dominant and recessive forms of Familial Hypercholesterolemia (example, Hobbs_1992, Martin-Campos_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <2% of normal LDL-receptor activity (Hobbs_1992). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV002347934	SCV002641659	pathogenic	Cardiovascular phenotype	2020-02-24	criteria provided, single submitter	clinical testing	The p.W4* pathogenic mutation (also known as c.11G>A), located in coding exon 1 of the LDLR gene, results from a G to A substitution at nucleotide position 11. This changes the amino acid from a tryptophan to a stop codon within coding exon 1. This variant (also referred to as FH Columbia-1 and Trp-18Term) and a different nucleotide substitution resulting in the same protein impact (c.12G>A, also known as FH Nanjing-1 and Trp-18Term) have been detected in familial hypercholesterolemia cohorts in the heterozygous, homozygous and compound heterozygous states (Hobbs HH et al. Hum. Mutat., 1992;1:445-66; Sun XM et al. Arterioscler. Thromb., 1994 Jan;14:85-94; Cenarro A et al. Hum. Mutat., 1998;11:413; Robles-Osorio L et al. Arch. Med. Res., 2006 Jan;37:102-8; Tejedor MT et al. Mol. Genet. Genomics, 2010 Jun;283:565-74; Garcia-Garcia AB et al. Atherosclerosis. 2011 Oct;218(2):423-30 Olfson E et al. PLoS ONE, 2015 Sep;10:e0135193). 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.
Revvity Omics, Revvity	RCV000237276	SCV003825377	pathogenic	Hypercholesterolemia, familial, 1	2022-12-19	criteria provided, single submitter	clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000237276	SCV000605996	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research