ClinVar Miner

Submissions for variant NM_000527.5(LDLR):c.2051C>T (p.Ala684Val)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002421827 SCV002727552 uncertain significance Cardiovascular phenotype 2018-03-30 criteria provided, single submitter clinical testing The p.A684V variant (also known as c.2051C>T), located in coding exon 14 of the LDLR gene, results from a C to T substitution at nucleotide position 2051. The alanine at codon 684 is replaced by valine, an amino acid with similar properties. Another alteration affecting the same amino acid, p.A684T (c.2050G>A), has been reported (using legacy nomenclature, p.A663T) in association with familial hypercholesterolemia (FH) (Khoo KL et al. Clin. Genet., 2000 Aug;58:98-105). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004007394 SCV004835576 uncertain significance Hypercholesterolemia, familial, 1 2023-11-20 criteria provided, single submitter clinical testing This missense variant (also known as p.Ala663Val in the mature protein) replaces alanine with valine at codon 684 of the LDLR protein. Computational prediction suggests that this variant may have 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 not been reported in individuals affected with LDLR-related disorders in the literature. This variant has been identified in 1/31408 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.

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