ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.1201C>G (p.Leu401Val) (rs146200173)

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Total submissions: 10
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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 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000255176 SCV000322301 pathogenic not provided 2016-08-25 criteria provided, single submitter clinical testing The L401V variant in the LDLR gene has been reported previously in the heterozygous state in multiple individuals with familial hypercholesterolemia (Leren et al., 1997; Vaca et al., 2011; Jannes et al., 2015). Note that Leren et al. described L401V using alternate nomenclature L380V (1997). The L401V variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L401V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue, L401H, was previously reported, using alternate nomenclature L308H and referred to as FH-Pori, in four unrelated individuals of Finnish descent with heterozygous familial hypercholesterolemia (Koivisto et al., 1995), supporting the functional importance of this region of the protein. Therefore, we interpret L401V as a known pathogenic variant.
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 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 2016-03-01 criteria provided, single submitter research
Invitae RCV000238417 SCV000627015 likely pathogenic Familial hypercholesterolemia 2017-06-03 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). 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. In summary, this variant is a rare missense change that has been reported in many affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000586642 SCV000697189 pathogenic Familial hypercholesterolemias 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 2016-03-01 criteria provided, single submitter research
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000238417 SCV000839994 likely pathogenic Familial hypercholesterolemia 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.
CSER_CC_NCGL; University of Washington Medical Center 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 no assertion criteria provided research

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