Submissions for variant NM_000527.5(LDLR):c.1478_1479del (p.Ser493fs)

dbSNP: rs869025453

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208069	SCV000264003	pathogenic	Hypercholesterolemia, familial, 1	2015-07-02	criteria provided, single submitter	clinical testing
LDLR-LOVD, British Heart Foundation	RCV000208069	SCV000295462	pathogenic	Hypercholesterolemia, familial, 1	2016-03-25	criteria provided, single submitter	literature only
Robarts Research Institute, Western University	RCV000208069	SCV000484798	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	RCV000208069	SCV000503356	pathogenic	Hypercholesterolemia, familial, 1	2016-12-16	criteria provided, single submitter	clinical testing	subjects mutated among 2600 FH index cases screened = 4 , family members = 2 with co-segregation
Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation	RCV000208069	SCV000540905	pathogenic	Hypercholesterolemia, familial, 1	2017-03-27	criteria provided, single submitter	clinical testing
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille	RCV000208069	SCV000583837	pathogenic	Hypercholesterolemia, familial, 1	2017-03-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000522258	SCV000617510	pathogenic	not provided	2023-05-23	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25911074, 8740919, 21865347, 7866407, 20145306, 7489239, 9974426, 11810272, 30586733, 29866529, 34040191, 32977124, 33269076, 33740630, 34037665, 33955087, 30710474, 28161202)
Invitae	RCV000780377	SCV000752413	pathogenic	Familial hypercholesterolemia	2023-08-30	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Ser493Cysfs*42) 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 premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7866407, 11810272, 20045108, 20145306, 21865347). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 222688).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780377	SCV000917580	pathogenic	Familial hypercholesterolemia	2018-05-07	criteria provided, single submitter	clinical testing	Variant summary: LDLR c.1478_1479delCT (p.Ser493CysfsX42) 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 (eg. c.1686G>A, p.Trp562X; c.2043C>A, p.Cys681X; c.2061dupC, p.Asn688fsX29). The variant allele was found at a frequency of 3.2e-05 in 30908 control chromosomes (gnomAD). The variant, c.1478_1479delCT, has been reported in the literature in multiple individuals affected with Familial Hypercholesterolemia (Cavanaugh_1994, Jensen_1996, Fouchier_2001, Romano_2011, Kusters_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, showing a 10%-30% of normal LDL uptake activity associated with this variant (Romano_2011). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II	RCV000208069	SCV001653638	pathogenic	Hypercholesterolemia, familial, 1	2021-05-24	criteria provided, single submitter	clinical testing	Reduced activity, in stimulated T- and EBV-transformed B-lymphocytes (with Ser123Pro).
Ambry Genetics	RCV002390558	SCV002697070	pathogenic	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The c.1478_1479delCT pathogenic mutation, located in coding exon 10 of the LDLR gene, results from a deletion of two nucleotides at nucleotide positions 1478 to 1479, causing a translational frameshift with a predicted alternate stop codon (p.S493Cfs*42). This mutation has been previously reported in association with familial hypercholesterolemia (Cavanaugh JA et al. Hum. Mutat., 1994;4:276-80; Schuster H et al. Arterioscler. Thromb. Vasc. Biol., 1995 Dec;15:2176-80; Bertolini S et al. Arterioscler. Thromb. Vasc. Biol., 1999 Feb;19:408-18; Chmara M et al. J. Appl. Genet., 2010;51:95-106; Romano M et al. J. Lipid Res., 2011 Nov;52:2095-100; Minicocci I et al. J. Pediatr., 2017 04;183:100-107.e3; Klaus G et al. Pediatr. Nephrol., 2018 Jul;33:1199-1208). 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.
PreventionGenetics, part of Exact Sciences	RCV003401115	SCV004105732	pathogenic	LDLR-related condition	2024-02-14	criteria provided, single submitter	clinical testing	The LDLR c.1478_1479delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser493Cysfs*42). This variant has been well-documented to be pathogenic for Hypercholesterolemia (Chmara et al. 2010. PubMed ID: 20145306; Bertolini et al. 2020. PubMed ID: 32977124. Table S2; Sturm et al. 2021. PubMed ID: 34037665. eTable 1). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in LDLR are expected to be pathogenic. This variant is interpreted as pathogenic.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000208069	SCV000606441	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research
Natera, Inc.	RCV000780377	SCV002086426	pathogenic	Familial hypercholesterolemia	2021-07-26	no assertion criteria provided	clinical testing