ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1474G>C (p.Asp492His) (rs373646964)

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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 RCV000238035 SCV000295459 likely pathogenic Familial hypercholesterolemia 1 2016-03-25 criteria provided, single submitter literature only
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587515 SCV000697198 likely pathogenic Familial hypercholesterolemia 2019-08-01 criteria provided, single submitter clinical testing Variant summary: LDLR c.1474G>C (p.Asp492His) results in a non-conservative amino acid change located in the LDLR class B repeat domain (IPR000033) 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 3.9e-06 in 258942 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1474G>C has been reported in the literature in individuals affected with Familial Hypercholesterolemia (Heath_1999, Khera_2019). In addition, other missense changes at this position, Asp492Asn and Asp492Gly, along with nearby codons, T491N, G496D, G496V, T497P, have been reported as pathogenic, suggesting this region is important for protein function. Furthermore, Jeon_2001, reports that mutations in this region are likely to disrupt the structure of the propeller and prevent efficient transport of the receptor to the cell surface leading to Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions (evaluation after 2014) cite the variant once as uncertain significance and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000587515 SCV000830403 pathogenic Familial hypercholesterolemia 2020-10-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with histidine at codon 492 of the LDLR protein (p.Asp492His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of familial hypercholesterolemia (PMID: 10208479, Invitae). This variant is also described as p.Asp471His (D471H) in the literature. ClinVar contains an entry for this variant (Variation ID: 251864). 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). This variant disrupts the p.Asp492 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 10230472, 23375686, 25487149, 25936317, 9763532, 16250003), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Color Health, Inc RCV000587515 SCV000909509 likely pathogenic Familial hypercholesterolemia 2019-03-22 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284639 SCV001470528 uncertain significance not provided 2019-10-21 criteria provided, single submitter clinical testing
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde,Academisch Medisch Centrum RCV000238035 SCV000606439 pathogenic Familial hypercholesterolemia 1 no assertion criteria provided research

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