ClinVar Miner

Submissions for variant NM_000527.4(LDLR):c.907C>T (p.Arg303Trp) (rs151207122)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CSER_CC_NCGL; University of Washington Medical Center RCV000148588 SCV000190302 uncertain significance Hypercholesterolaemia 2014-06-01 no assertion criteria provided research
GeneDx RCV000657894 SCV000779658 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the LDLR gene. The R303W variant (reported as R282W due to the use of alternate nomenclature) has been reported in one patient with moderate hypercholesterolemia (Arca et al., 1998). The R303W variant is observed in 9/24012 (0.04%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). Nonetheless, the R303W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000791388 SCV000825564 uncertain significance Familial hypercholesterolemias 2018-12-04 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.
LDLR-LOVD, British Heart Foundation RCV000238462 SCV000295044 likely pathogenic Familial hypercholesterolemia 2016-03-25 criteria provided, single submitter literature only
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238462 SCV000606263 pathogenic Familial hypercholesterolemia no assertion criteria provided research

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