ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1294C>G (p.Leu432Val) (rs730882100)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237224 SCV000295347 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000161983 SCV000697194 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The LDLR c.1294C>G (p.Leu432Val) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/120904 control chromosomes at a frequency of 0.0000248, which does not exceed the estimated maximal expected allele frequency of a pathogenic LDLR variant (0.0025031). This variant has been reported in affected individuals including FH, MI, and CAD, all without strong evidence for causality (i.e. co-segregation data). In addition, LDLR-LOVD, British Heart Foundation classified this variant as likely pathogenic, without evidence to independently evaluate. One published functional study showed that overexpression of p.Leu432Val resulted in intact cellular LDL uptake comparable to wild-type, although authors did list variant as a hypomorphic variant and speculated that the compound heterozygosity of two hypomorphic variants (Y465N and L432V for example) could impair receptor activities in the range of a classic FH-mutant (Thormaehlen_2015). JoJo Genetics noted that variant of interest often co-occured with Y465N (Y444N in legacy name) although the phase not well established. Taken together and due to conflicting lines of evidence, this variant is classified as VUS until more evidence becomes available.
Color Health, Inc RCV001182459 SCV001347903 uncertain significance Familial hypercholesterolemia 2020-03-20 criteria provided, single submitter clinical testing
Invitae RCV001182459 SCV001413767 uncertain significance Familial hypercholesterolemia 2020-04-27 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 432 of the LDLR protein (p.Leu432Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs730882100, ExAC 0.006%). This variant has been observed in several individuals with clinical features of familial hypercholesterolemia, including in some individuals with a second variant in LDLR (PMID: 10090484, 25647241, 25487149). ClinVar contains an entry for this variant (Variation ID: 183111). This variant is also described as L411V in the literature. 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Dept. of Genetics and Pharmacogenomics, Merck Research Labs RCV000161983 SCV000189558 not provided not provided no assertion provided in vitro
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000237224 SCV000606383 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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