Submissions for variant NM_174936.4(PCSK9):c.1954A>G (p.Asn652Asp)

gnomAD frequency: 0.00003  dbSNP: rs201280059

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000338615	SCV000358263	uncertain significance	Hypobetalipoproteinemia	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001093779	SCV000358264	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000776463	SCV000912012	uncertain significance	Familial hypercholesterolemia	2022-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 652 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 shown that this variant causes increased PCSK9 proteolytic activity in vitro (PMID: 29259136). This variant has been reported in an individual affected with premature myocardial infarction (PMID: 30971288) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 16/282254 chromosomes (15/19938 East Asian 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	RCV001093779	SCV003251096	likely benign	Hypercholesterolemia, autosomal dominant, 3	2024-05-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004021443	SCV004091580	likely benign	Cardiovascular phenotype	2023-09-07	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV001093779	SCV004845358	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 652 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 shown that this variant causes increased PCSK9 proteolytic activity in vitro (PMID: 29259136). This variant has been reported in an individual affected with premature myocardial infarction (PMID: 30971288) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 16/282254 chromosomes (15/19938 East Asian 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.