Submissions for variant NM_174936.4(PCSK9):c.503C>T (p.Ala168Val)

gnomAD frequency: 0.00001  dbSNP: rs770592607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001189882	SCV001357255	uncertain significance	Familial hypercholesterolemia	2024-01-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 168 of the PCSK9 protein. Computational prediction tools indicate that this variant has a neutral impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with familial hypercholesterolemia (PMID: 31491741). This variant has been identified in 3/282534 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	RCV001863008	SCV002292232	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-05-22	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 926970). 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. This missense change has been observed in individual(s) with clinical features of familial hypercholesterolemia (PMID: 31491741). This variant is present in population databases (rs770592607, gnomAD 0.006%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 168 of the PCSK9 protein (p.Ala168Val).
Ambry Genetics	RCV003353199	SCV004056437	uncertain significance	Cardiovascular phenotype	2023-06-29	criteria provided, single submitter	clinical testing	The p.A168V variant (also known as c.503C>T), located in coding exon 3 of the PCSK9 gene, results from a C to T substitution at nucleotide position 503. The alanine at codon 168 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort; however, clinical details were limited (Hori M et al. Atherosclerosis, 2019 Oct;289:101-108). This amino acid position is not well conserved in available vertebrate species. 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.
All of Us Research Program, National Institutes of Health	RCV001863008	SCV004842326	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 168 of the PCSK9 protein. Computational prediction tool 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. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 3/282534 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.