ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1156G>T (p.Asp386Tyr)

dbSNP: rs1402951356
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Familial Hypercholesterolemia Variant Curation Expert Panel RCV000508869 SCV002506404 uncertain significance Hypercholesterolemia, familial, 1 2022-03-25 reviewed by expert panel curation The NM_000527.5 (LDLR):c.1156G>T (p.Asp386Tyr) variant is classified as Uncertain significance - insufficient evidence for Familial Hypercholesterolemia by applying evidence codes (PM2, PP3) as defined by the ClinGen Familial Hypercholesterolemia Expert Panel LDLR-specific variant curation guidelines (https://doi.org/10.1016/j.gim.2021.09.012). The supporting evidence is as follows: PM2: PopMax MAF = 0.00001 in European (Non-Finnish) population in gnomAD (gnomAD v2.1.1). PP3: REVEL score = 0.883, it is above the threshold of 0.75.
Fundacion Hipercolesterolemia Familiar RCV000508869 SCV000607566 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV001183223 SCV001348898 uncertain significance Familial hypercholesterolemia 2019-06-27 criteria provided, single submitter clinical testing This missense variant (also known as p.Asp365Tyr in the mature protein) replaces aspartic acid with tyrosine at codon 386 of the LDLR protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/251080 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Invitae RCV001183223 SCV003442671 uncertain significance Familial hypercholesterolemia 2021-08-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 386 of the LDLR protein (p.Asp386Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant LDLR-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 440627). 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. 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508869 SCV000606339 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research

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