Submissions for variant NM_174936.4(PCSK9):c.1948G>A (p.Val650Ile)

gnomAD frequency: 0.00003  dbSNP: rs767706622

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Robarts Research Institute, Western University	RCV000408832	SCV000484819	uncertain significance	Hypercholesterolemia, familial, 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000806410	SCV000946406	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 650 of the PCSK9 protein (p.Val650Ile). This variant is present in population databases (rs767706622, gnomAD 0.01%). 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: 369877). 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.
Color Diagnostics, LLC DBA Color Health	RCV003581652	SCV004358828	uncertain significance	Familial hypercholesterolemia	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 650 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). A functional study has reported that this variant increased PCSK9 processing (PMID: 29728531). This variant has not been reported in individuals affected with PCSK9-related disorders in the literature. This variant has been identified in 5/282016 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.
All of Us Research Program, National Institutes of Health	RCV000806410	SCV004845336	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces valine with isoleucine at codon 650 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). A functional study has reported that this variant increased PCSK9 processing (PMID: 29728531). This variant has not been reported in individuals affected with familial hypercholesterolemia in the literature. This variant has been identified in 5/282016 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.