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

dbSNP: rs869025453

Total submissions: 18

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	2025-05-12	criteria provided, single submitter	clinical testing	Identified in multiple patients with FH in published literature (PMID: 7866407, 20145306, 28161202); Frameshift variant predicted to result in protein truncation or nonsense mediated decay 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, 34297352, 33955087, 30710474, 20045108, 28161202)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000780377	SCV000752413	pathogenic	Familial hypercholesterolemia	2025-01-01	criteria provided, single submitter	clinical testing	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 variant is present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with familial hypercholesterolemia (PMID: 7866407, 11810272, 20045108, 20145306, 21865347). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this LDLR variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 363,995 individuals referred to our laboratory for LDLR testing. For these reasons, this variant has been classified as Pathogenic.
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.
All of Us Research Program, National Institutes of Health	RCV000208069	SCV004840109	pathogenic	Hypercholesterolemia, familial, 1	2023-11-14	criteria provided, single submitter	clinical testing	The c.1478_1479del (p.Ser493Cysfs*42) variant in the LDLR gene introduces a premature translation termination codon resulting in an absent or disrupted protein product. The variant has been reported in several individuals (>10) with familial hypercholesterolemia (FH) (PMID:7866407, 8740919, 11810272, 23833242, 28161202, 20145306, 33269076, 33794673, 19446849). This variant has also been reported in compound heterozygous status (with p.Ser123Pro) in an individual with FH, and in-vitro functional studies using patient-derived EBV transformed cell lines showed residual LDLR activity of about 32% compared to the normal controls (PMID: 20045108). This variant has been observed in homozygous status in an individual with severe FH (LDL-C: 17.6mmol/dL) (PMID: 29502162). Loss-of-function variants in LDLR are known to be pathogenic (PMID: 33740630, 15321837, 20809525, 28645073). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID:11810272) and by several ClinVar submitters (ClinVar ID: 222689, 432366). This variant is found to be rare (1/31342; 0.00003191) in the general population database (gnomAD) and interpreted as pathogenic by multiple submitters in the ClinVar (ClinVar ID: 222688). Therefore, the c.1478_1479del (p.Ser493Cysfs*42) variant in the LDLR gene is classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000208069	SCV005399520	pathogenic	Hypercholesterolemia, familial, 1	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with both familial hypercholesterolemia (MIM#143890) and LDL cholesterol level QTL2 (MIM#143890). (I) 0108 - This gene is associated with both recessive and dominant disease. Individuals with biallelic pathogenic variants are reported to have an earlier and more severe onset of disease (GeneReviews). (I) 0112 - The condition associated with this gene has incomplete penetrance (GeneReviews). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in more than ten individuals with familial hypercholesterolaemia, as both heterozygous in individuals with autosomal dominant disease and as compound heterozygous in individuals with more severe autosomal recessive disease (ClinVar, LOVD, PMIDs: 20045108, 33269076, 31947532, 33794673). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV005245492	SCV005894811	pathogenic	Hypercholesterolemia	2025-01-29	criteria provided, single submitter	clinical testing	Observed in a heterozygous state, at our lab, in a patient with matching phenotype. ACMG criteria used: PVS1, PS4, PM2, PP4
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV005404394	SCV006066099	pathogenic	Dyslipidemia	2024-08-08	criteria provided, single submitter	clinical testing	PVS1, PS4, PM2, PM3, PP1, PP4
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
PreventionGenetics, part of Exact Sciences	RCV003401115	SCV004105732	pathogenic	LDLR-related disorder	2024-02-14	no assertion criteria provided	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.