ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.654A>T (p.Arg218Ser)

dbSNP: rs970575319
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group, Instituto Nacional de Saude Doutor Ricardo Jorge RCV000505213 SCV000599425 uncertain significance Hypercholesterolemia, familial, 1 2016-03-01 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV001865640 SCV002240628 pathogenic Hypercholesterolemia, autosomal dominant, 3 2021-09-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 218 of the PCSK9 protein (p.Arg218Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with familial hypercholesterolemia (PMID: 16211558). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 438334). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCSK9 protein function. Experimental studies have shown that this missense change affects PCSK9 function (PMID: 15358785, 16912035, 18039650, 21147780). This variant disrupts the p.Arg218 amino acid residue in PCSK9. Other variant(s) that disrupt this residue have been observed in individuals with PCSK9-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV004772947 SCV005385482 likely pathogenic not provided 2024-04-19 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15358785, 17461796, 16211558, 33955087, 16912035)

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