Submissions for variant NM_174936.4(PCSK9):c.2050C>G (p.Leu684Val)

gnomAD frequency: 0.00004  dbSNP: rs201557607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775306	SCV000909565	uncertain significance	Familial hypercholesterolemia	2023-04-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 684 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 PCSK9-related disorders in the literature. This variant has been identified in 17/247026 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	RCV001232731	SCV001405299	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 684 of the PCSK9 protein (p.Leu684Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs201557607, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). 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: 630175). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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.
Ambry Genetics	RCV002422659	SCV002726541	uncertain significance	Cardiovascular phenotype	2022-01-07	criteria provided, single submitter	clinical testing	The p.L684V variant (also known as c.2050C>G), located in coding exon 12 of the PCSK9 gene, results from a C to G substitution at nucleotide position 2050. The leucine at codon 684 is replaced by valine, 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.
All of Us Research Program, National Institutes of Health	RCV001232731	SCV004846362	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 684 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 been identified in 17/247026 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.