Submissions for variant NM_174936.4(PCSK9):c.884G>A (p.Arg295His)

gnomAD frequency: 0.00001  dbSNP: rs775707869

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179034	SCV001343608	uncertain significance	Familial hypercholesterolemia	2023-12-04	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces arginine with histidine at codon 295 of the PCSK9 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/233652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003500646	SCV004264729	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2022-12-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 295 of the PCSK9 protein (p.Arg295His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 920358). 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 not expected to disrupt 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.
All of Us Research Program, National Institutes of Health	RCV003500646	SCV005431387	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-04-16	criteria provided, single submitter	clinical testing	Variant of Uncertain Significance due to insufficient evidence: This missense variant replaces arginine with histidine at codon 295 of the PCSK9 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 2/233652 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively.