ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.1936C>A (p.Leu646Ile)

dbSNP: rs779940524
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
LDLR-LOVD, British Heart Foundation RCV000238167 SCV000295760 likely pathogenic Hypercholesterolemia, familial, 1 2016-03-25 criteria provided, single submitter literature only
AiLife Diagnostics, AiLife Diagnostics RCV002223828 SCV002501984 uncertain significance not provided 2022-02-11 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000238167 SCV004821033 uncertain significance Hypercholesterolemia, familial, 1 2023-03-23 criteria provided, single submitter clinical testing This missense variant (also known as p.Leu625Ile in the mature protein) replaces leucine with isoleucine at codon 646 of the LDLR protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 2 individuals affected with familial hypercholesterolemia (PMID: 24373485) and in an individual affected with early-onset myocardial infarction (PMID: 25487149). This variant has been identified in 1/251476 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics RCV004992128 SCV005609297 uncertain significance Cardiovascular phenotype 2024-11-08 criteria provided, single submitter clinical testing The p.L646I variant (also known as c.1936C>A), located in coding exon 13 of the LDLR gene, results from a C to A substitution at nucleotide position 1936. The leucine at codon 646 is replaced by isoleucine, an amino acid with highly similar properties. This variant was has been detected in a familial hypercholesterolemia cohort (Komarova TY et al. BMC Med Genet, 2013 Dec;14:128). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.

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