ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2324T>C (p.Val775Ala)

gnomAD frequency: 0.00003  dbSNP: rs780300776
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000800276 SCV000939981 uncertain significance Familial hypercholesterolemia 2018-09-03 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 775 of the LDLR protein (p.Val775Ala). The valine residue is weakly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs780300776, ExAC 0.004%). This variant has not been reported in the literature in individuals with LDLR-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Color Diagnostics, LLC DBA Color Health RCV000800276 SCV001344611 likely benign Familial hypercholesterolemia 2018-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV002455982 SCV002736451 likely benign Cardiovascular phenotype 2023-01-10 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508779 SCV000606633 benign Hypercholesterolemia, familial, 1 no assertion criteria provided research

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