ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.581G>A (p.Arg194Gln)

gnomAD frequency: 0.00004  dbSNP: rs748155397
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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 RCV001189885 SCV001357258 uncertain significance Familial hypercholesterolemia 2022-12-01 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 194 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). One functional study showed that this variant may not alter PCSK9 processing (PMID: 29259136). This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 4/282686 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 RCV004010398 SCV004840480 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces arginine with glutamine at codon 194 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 reported that this variant does not affect PCSK9 protein processing (PMID: 29259136). This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 4/282686 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV004010398 SCV005829547 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2024-03-06 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 194 of the PCSK9 protein (p.Arg194Gln). This variant is present in population databases (rs748155397, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with PCSK9-related conditions. ClinVar contains an entry for this variant (Variation ID: 926972). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PCSK9 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.

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