ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.2014G>A (p.Val672Met)

gnomAD frequency: 0.00001  dbSNP: rs892210400
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000644535 SCV000766235 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2021-08-30 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 672 of the PCSK9 protein (p.Val672Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. 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 methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001190905 SCV001358540 uncertain significance Familial hypercholesterolemia 2023-01-26 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 672 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 1/249588 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.
Fulgent Genetics, Fulgent Genetics RCV000644535 SCV002784287 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2021-08-27 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000644535 SCV004845536 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 672 of the PCSK9 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 1/249588 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 RCV004649238 SCV005147451 uncertain significance Cardiovascular phenotype 2024-04-21 criteria provided, single submitter clinical testing The p.V672M variant (also known as c.2014G>A), located in coding exon 12 of the PCSK9 gene, results from a G to A substitution at nucleotide position 2014. The valine at codon 672 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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