ClinVar Miner

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

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Total submissions: 11
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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 Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000255176 SCV000322301 likely pathogenic not provided 2021-08-19 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); Reported in ClinVar (ClinVar Variant ID# 161267; Landrum et al., 2016); 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: 33740630, 32715071, 32041611, 26582918, 30586733, 9104431, 25461735, 12124988, 31447099, 23833242, 24507775, 21722902, 23669246, 25637381)
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 Familial hypercholesterolemia 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 Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Invitae RCV000586642 SCV000627015 pathogenic Familial hypercholesterolemia 2020-07-23 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 401 of the LDLR protein (p.Leu401Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs146200173, ExAC 0.02%). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 9104431, 21722902, 25461735, 24507775). It is also known as p.Leu380Val in the literature. This variant has been reported in individuals in the Universal Mutation Database (PMID: 12124988) and has an entry in ClinVar (Variation ID: 161267). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. 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, 19843101, 15701167, 11810272). 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 Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000238417 SCV000839994 likely pathogenic Familial hypercholesterolemia 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 Health, Inc 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.
CSER _CC_NCGL, University of Washington RCV000148572 SCV000190285 likely pathogenic Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238417 SCV000606356 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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