ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1201C>G (p.Leu401Val)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238417 SCV000295293 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000255176 SCV000322301 likely pathogenic not provided 2023-08-08 criteria provided, single submitter clinical testing Reported in 2 cases and 1 control in a study of individuals with a history of early-onset myocardial infarction (Khera et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12124988, 25461735, 9104431, 30586733, 32041611, 32715071, 33740630, 25637381, 23669246, 21722902, 24507775, 23833242, 31447099, 34040191, 21957200, 26582918, 33955087, 22683370, 34037665)
Centre de Génétique Moléculaire et Chromosomique, Unité de génétique de l'Obésité et des Dyslipidémies, APHP, GH Hôpitaux Universitaires Pitié-Salpêtrière / Charles-Foix RCV000238417 SCV000503313 uncertain significance Hypercholesterolemia, familial, 1 2016-12-16 criteria provided, single submitter clinical testing subject mutated among 2600 FH index cases screened = 1 compound heterozygous on LDL Apheresis /FH-Norvege / Software predictions: Conflicting
Laboratory of Genetics and Molecular Cardiology, University of São Paulo RCV000238417 SCV000588564 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000586642 SCV000627015 pathogenic Familial hypercholesterolemia 2024-01-11 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 401 of the LDLR protein (p.Leu401Val). This variant is present in population databases (rs146200173, gnomAD 0.02%). This missense change has been observed in individuals with hypercholesterolemia (PMID: 9104431, 12124988, 21722902, 24507775, 25461735). This variant is also known as p.Leu380Val. ClinVar contains an entry for this variant (Variation ID: 161267). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt LDLR protein function with a positive predictive value of 95%. This variant disrupts the p.Leu401 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7573037, 11810272, 15701167, 19843101). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586642 SCV000697189 pathogenic Familial hypercholesterolemia 2016-04-28 criteria provided, single submitter clinical testing Variant summary: The c.1201C>G variant affects a conserved nucleotide, resulting in amino acid change from Leu to Val. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant is found in 2/119858 control chromosomes at a frequency of 0.0000167, which does not exceed maximal expected frequency of a pathogenic allele (0.0012508) to exclude pathogenicity. The variant was reported in several FH patients and one study reported the variant to co-segregate with hypercholesterolemia (Leren_JIM_19970) indicating pathogenicity. In addition, a clinical laboratory and a reputable database classify this variant as Likely pathogenic / Disease causing. Taken together, this variant was classified as Pathogenic.
Iberoamerican FH Network RCV000238417 SCV000748051 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000238417 SCV000839994 likely pathogenic Hypercholesterolemia, familial, 1 2018-05-11 criteria provided, single submitter clinical testing The c.1201C>G (p.Leu401Val) variant in the LDLR gene has been observed in multiple individuals with familial hypercholesteromeia (PMID: 9104431, 21722902, 25461735). In addition, a missense variant at the same residue, p.Leu401His, has been previously reported in other affected individuals (PMID: 7573037, 11810272,15701167). Therefore, this variant in the LDLR gene is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health RCV000586642 SCV001347900 likely pathogenic Familial hypercholesterolemia 2020-08-05 criteria provided, single submitter clinical testing This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity RCV000238417 SCV002022661 likely pathogenic Hypercholesterolemia, familial, 1 2022-08-31 criteria provided, single submitter clinical testing
AiLife Diagnostics, AiLife Diagnostics RCV000255176 SCV002502785 likely pathogenic not provided 2021-11-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV002345455 SCV002650517 likely pathogenic Cardiovascular phenotype 2021-07-16 criteria provided, single submitter clinical testing The p.L401V variant (also known as c.1201C>G), located in coding exon 9 of the LDLR gene, results from a C to G substitution at nucleotide position 1201. The leucine at codon 401 is replaced by valine, an amino acid with highly similar properties. This alteration, also referred to as L380V, has been reported in hypercholesterolemia and early onset myocardial infarction cohorts (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94; Vaca G et al. Atherosclerosis, 2011 Oct;218:391-6; Lange LA et al. Am. J. Hum. Genet., 2014 Feb;94:233-45; Jannes CE et al. Atherosclerosis, 2015 Jan;238:101-7; Khera AV et al. Circulation, 2019 03;139:1593-1602). This alteration was also described to segregate with the disease (Leren TP et al. J. Intern. Med., 1997 Mar;241:185-94). This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res., 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000238417 SCV003932178 likely pathogenic Hypercholesterolemia, familial, 1 2023-03-06 criteria provided, single submitter clinical testing PS3_Moderate, PM2, PM5_Supporting, PP3
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255176 SCV004219938 likely pathogenic not provided 2022-08-10 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.0002 (5/24928 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431 (1997), 21722902 (2011), 25461735 (2015), 32715071(2020), 34037665 (2021) and 33740630 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic.
All of Us Research Program, National Institutes of Health RCV000238417 SCV004820276 likely pathogenic Hypercholesterolemia, familial, 1 2023-11-14 criteria provided, single submitter clinical testing This missense variant (also known as p.Leu380Val in the mature protein) replaces leucine with valine at codon 401 of the LDLR protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with familial hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 32715071) and segregated with disease in multiple families (PMID: 9104431). This variant has been identified in 7/282282 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CSER _CC_NCGL, University of Washington RCV002051660 SCV000190285 likely pathogenic Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000238417 SCV000606356 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV000586642 SCV002086413 pathogenic Familial hypercholesterolemia 2020-01-22 no assertion criteria provided clinical testing

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