ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1870G>A (p.Val624Met)

gnomAD frequency: 0.00001  dbSNP: rs760437822
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001176339 SCV001340283 uncertain significance Familial hypercholesterolemia 2023-04-27 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 624 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). A functional study has shown that the variant causes increased proteolytic activity (PMID: 29259136). This variant has been reported in an individual affected with familial hypercholesterolemia (PMID: 17316651). This variant has been identified in 10/279050 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.
All of Us Research Program, National Institutes of Health RCV004006289 SCV004844510 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2024-08-06 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 624 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. A functional study has shown that the variant causes increased proteolytic activity (PMID: 29259136). This variant has been reported in an individual with high LDL-C levels (PMID: 17316651). This variant has been identified in 10/279050 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 RCV004032994 SCV005001972 uncertain significance Cardiovascular phenotype 2023-11-20 criteria provided, single submitter clinical testing The c.1870G>A (p.V624M) alteration is located in coding exon 12 of the PCSK9 gene. This alteration results from a G to A substitution at nucleotide position 1870, causing the valine (V) at amino acid position 624 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of 0.004% (10/279050) total alleles studied. The highest observed frequency was 0.02% (4/19872) of East Asian alleles. This variant was reported in a Japanese individual undergoing treatment for elevated LDL-C levels; however clinical details were limited and an additional alteration in PCSK9 was identified in this case (Miyake, 2008). This amino acid position is well conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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