ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.907C>T (p.Arg303Trp)

gnomAD frequency: 0.00009  dbSNP: rs151207122
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000238462 SCV001960917 uncertain significance Hypercholesterolemia, familial, 1 2021-06-08 reviewed by expert panel curation The NM_000527.5(LDLR):c.907C>T (p.Arg303Trp) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1101/2021.03.17.21252755). The supporting evidence is as follows: PP3 - REVEL = 0.815. It is above 0.75, so PP3 is Met.
LDLR-LOVD, British Heart Foundation RCV000238462 SCV000295044 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
GeneDx RCV000657894 SCV000779658 uncertain significance not provided 2022-06-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.(R282W); This variant is associated with the following publications: (PMID: 25637381, 25487149, 31106297, 32977124, 32719484, 33955087, 24507775, 28965616, 9544746, 35741760, 34040191)
Invitae RCV000791388 SCV000825564 uncertain significance Familial hypercholesterolemia 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 303 of the LDLR protein (p.Arg303Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs151207122, ExAC 0.03%). This variant has been reported in individuals affected with hypercholesterolemia (PMID: 9544746, 24507775, 28965616). This variant is also known as p.Arg282Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 161281). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781501 SCV000919581 uncertain significance not specified 2018-05-23 criteria provided, single submitter clinical testing Variant summary: LDLR c.907C>T (p.Arg303Trp) results in a non-conservative amino acid change located in the Low-density lipoprotein (LDL) receptor class A repeat of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 277062 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in LDLR causing Familial Hypercholesterolemia (4e-05 vs 1.30e-03), allowing no conclusion about variant significance. The variant, c.907C>T, has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Arca_1997, Pirillo_2017), although without strong evidence for pathogenicity such as cosegregation with disease in families, thus these reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. The Arg303 codon and adjacent codons have been implicated in Familial Hypercholesterolemia (e.g., p.303Q p.C302R, p.C302W, p.D304N, p.D304E), suggesting the codon and region may be a mutational hotspot and critical for protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submissions to ClinVar show differing interpretations: one VUS, one likely pathogenic, and one pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Color Health, Inc RCV000791388 SCV001346462 uncertain significance Familial hypercholesterolemia 2021-04-13 criteria provided, single submitter clinical testing This missense variant (also known as p.Arg282Trp in the mature protein) replaces arginine with tryptophan at codon 303 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 reported for this variant. This variant has been reported in several individuals affected with hypercholesterolemia (PMID: 9544746, 28965616). This variant has been identified in 13/282676 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Brunham Lab, Centre for Heart and Lung Innovation,University of British Columbia RCV000238462 SCV001432670 uncertain significance Hypercholesterolemia, familial, 1 2019-05-10 criteria provided, single submitter research
Mayo Clinic Laboratories,Mayo Clinic RCV000657894 SCV001715243 uncertain significance not provided 2021-02-11 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV002051674 SCV000190302 uncertain significance Hypercholesterolemia 2014-06-01 no assertion criteria provided research
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238462 SCV000606263 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Natera, Inc. RCV000791388 SCV002086393 uncertain significance Familial hypercholesterolemia 2020-09-24 no assertion criteria provided clinical testing

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