Submissions for variant NM_000527.5(LDLR):c.1730G>A (p.Trp577Ter)

dbSNP: rs138947766

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix	RCV000417240	SCV000503401	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 5 , family members = 4 with co-segregation / Other nonsens mutation at same codon with < 2% LDLR Activity
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000417240	SCV000583871	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
Fundacion Hipercolesterolemia Familiar	RCV000417240	SCV000607633	pathogenic	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000996757	SCV001151666	likely pathogenic	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001049063	SCV001213097	pathogenic	Familial hypercholesterolemia	2019-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp577*) in the LDLR gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with familial hypercholesterolemia (PMID: 23680767, 24507775, 26802169). ClinVar contains an entry for this variant (Variation ID: 375821). A different variant (c.1731G>A) giving rise to the same protein effect observed here (p.Trp577*) has been determined to be pathogenic (PMID: 1301956, Invitae). This suggests that this variant is also likely to be causative of disease. Loss-of-function variants in LDLR are known to be pathogenic (PMID: 20809525). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000417240	SCV001422913	pathogenic	Hypercholesterolemia, familial, 1	2020-01-22	criteria provided, single submitter	curation	The p.Trp577Ter (sometimes called p.Trp556Ter) variant in LDLR has been reported in at least 5 individuals (including 1 Russian, 1 French, and 1 from the UK) with Familial Hypercholesterolemia in ClinVar and the literature (Variation ID: 375821; PMID: 1301956, 23680767, 26802169), and was absent from large population studies. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported pathogenic in ClinVar (Variation ID: 375821). This nonsense variant leads to a premature termination codon at position 577, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the LDLR gene is an established disease mechanism in Familial Hypercholesterolemia. Multiple variants in the same position as p.Trp577Ter have been reported in association with disease in ClinVar, suggesting that this variant is in a mutational hot spot and slightly supports pathogenicity (Variation ID: 252001, 252000, 252003, 406163, 252004, 226370). One pathogenic variant with the same amino acid change as this variant, c.1731G>A, has been reported in association with disease in ClinVar, supporting that this variant may be pathogenic (Variation ID: 226370). The phenotype of an individual homozygous for this variant is highly specific for Familial Hypercholesterolemia with <2% LDL receptor activity (PMID: 1301956). Individuals who are homozygous for pathogenic variants are known to have a more severe phenotype than heterozygous individuals. In summary, this variant meets criteria to be classified as pathogenic for Familial Hypercholesterolemia in an autosomal dominant manner based on the predicted impact of the variant and another pathogenic variant with a different nucleotide change but the same amino acid change. ACMG/AMP Criteria applied: PVS1, PS1, PM2, PM1_Supporting, PS4_Supporting, PP4 (Richards 2015).
Ambry Genetics	RCV002411282	SCV002715670	pathogenic	Cardiovascular phenotype	2022-10-19	criteria provided, single submitter	clinical testing	The p.W577* pathogenic mutation (also known as c.1730G>A), located in coding exon 12 of the LDLR gene, results from a G to A substitution at nucleotide position 1730. This changes the amino acid from a tryptophan to a stop codon within coding exon 12. This variant has been detected in several individuals with familial hypercholesterolemia (Vandrovcova J et al. Genet Med, 2013 Dec;15:948-57; Lange LA et al. Am J Hum Genet, 2014 Feb;94:233-45; Wintjens R et al. J Lipid Res, 2016 Mar;57:482-91; Rieck L et al. Clin Genet, 2020 11;98:457-467). 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.