Submissions for variant NM_174936.4(PCSK9):c.1447C>G (p.Leu483Val)

dbSNP: rs1570307690

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810200	SCV000950393	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2018-12-17	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has been observed in an individual affected with familial hypercholesterolemia (Invitae). This variant has also been observed in a family with hypobetalipoproteinemia; however, this variant was observed in homozygosis in an unaffected family member and different PCSK9 variants segregated in this family (PMID: 19762784). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 483 of the PCSK9 protein (p.Leu483Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. 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.
Color Diagnostics, LLC DBA Color Health	RCV001188926	SCV001356110	uncertain significance	Familial hypercholesterolemia	2022-10-11	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 483 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.
Ambry Genetics	RCV002390629	SCV002700792	uncertain significance	Cardiovascular phenotype	2022-09-14	criteria provided, single submitter	clinical testing	The p.L483V variant (also known as c.1447C>G), located in coding exon 9 of the PCSK9 gene, results from a C to G substitution at nucleotide position 1447. The leucine at codon 483 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported in a normolipidemic individual and an individual with concerns for familial hypobetalipoproteinemia (Cariou B et al. Arterioscler Thromb Vasc Biol, 2009 Dec;29:2191-7). 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV003480853	SCV004227853	uncertain significance	not provided	2022-06-15	criteria provided, single submitter	clinical testing	BP4, PM2
All of Us Research Program, National Institutes of Health	RCV000810200	SCV004834678	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 483 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.