Submissions for variant NM_174936.4(PCSK9):c.1695C>G (p.His565Gln)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV003377699	SCV004098459	uncertain significance	Cardiovascular phenotype	2023-06-18	criteria provided, single submitter	clinical testing	The p.H565Q variant (also known as c.1695C>G), located in coding exon 11 of the PCSK9 gene, results from a C to G substitution at nucleotide position 1695. The histidine at codon 565 is replaced by glutamine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778115	SCV004641114	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 565 of the PCSK9 protein (p.His565Gln). 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: 2625020). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The glutamine 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.
All of Us Research Program, National Institutes of Health	RCV003778115	SCV004832219	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with glutamine at codon 565 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 familial hypercholesterolemia in the literature. This variant has not been identified 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.