ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1277T>C (p.Leu426Pro)

dbSNP: rs879254851
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000237865 SCV000295337 likely benign Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
U4M - Lille University & CHRU Lille, Université de Lille - CHRU de Lille RCV000237865 SCV000583815 pathogenic Hypercholesterolemia, familial, 1 2017-03-30 criteria provided, single submitter clinical testing
Invitae RCV001350143 SCV001544523 likely pathogenic Familial hypercholesterolemia 2022-05-27 criteria provided, single submitter clinical testing This missense change has been observed in individuals with familial hypercholesterolemia (PMID: 9763532, 25775905, 33269076; Invitae). This variant is also known as L405P. ClinVar contains an entry for this variant (Variation ID: 251763). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Leu426 amino acid residue in LDLR. Other variant(s) that disrupt this residue have been observed in individuals with LDLR-related conditions (PMID: 28353356), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 426 of the LDLR protein (p.Leu426Pro).
Ambry Genetics RCV002446478 SCV002683170 pathogenic Cardiovascular phenotype 2019-11-08 criteria provided, single submitter clinical testing The p.L426P pathogenic mutation (also known as c.1277T>C), located in coding exon 9 of the LDLR gene, results from a T to C substitution at nucleotide position 1277. The leucine at codon 426 is replaced by proline, an amino acid with similar properties. This mutation (described as legacy p.L405P) has been reported in an individual with familial hypercholesterolemia (FH) (Mak YT et al. Arterioscler. Thromb. Vasc. Biol., 1998 Oct;18:1600-5). Based on internal structural assessment, this alteration disrupts the beta-propeller domain of LDLR (Lo Surdo P et al. EMBO Rep., 2011 Dec;12:1300-5). An alternate amino acid substitution at this position, p.L426R, was also reported in an FH cohort, suggesting this position is a hotspot (Rubba P et al. Eur J Prev Cardiol, 2017 07;24:1051-1059). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genetics and Molecular Pathology, SA Pathology RCV000237865 SCV002761840 likely pathogenic Hypercholesterolemia, familial, 1 2022-07-06 criteria provided, single submitter clinical testing

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