Submissions for variant NM_174936.4(PCSK9):c.158C>G (p.Ala53Gly)

dbSNP: rs11583680

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001099061	SCV001255476	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001100867	SCV001257411	uncertain significance	Hypobetalipoproteinemia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Color Diagnostics, LLC DBA Color Health	RCV001181024	SCV001346078	uncertain significance	Familial hypercholesterolemia	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 53 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 been reported in double heterozygous state with a known pathogenic LDLR variant in two related individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious variants (PMID: 27919364). This variant has been identified in 4/223722 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251365	SCV001426937	uncertain significance	not specified	2020-07-20	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.158C>G (p.Ala53Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 192322 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.158C>G has been reported in the literature in two individuals affected with Autosomal dominant hypercholesterolemia who also carried another pathogenic variant (LDLR c.1285G>A, p.Val429Met) (Sjouke_2016). The report does not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance
Ambry Genetics	RCV002404323	SCV002708361	uncertain significance	Cardiovascular phenotype	2022-06-29	criteria provided, single submitter	clinical testing	The p.A53G variant (also known as c.158C>G), located in coding exon 1 of the PCSK9 gene, results from a C to G substitution at nucleotide position 158. The alanine at codon 53 is replaced by glycine, an amino acid with similar properties. This alteration has been reported in a familial hypercholesterolemia (FH) cohort; however, an additional alteration was detected in an associated gene (Sjouke B et al. J Clin Lipidol Sep;10:1462-1469). Additionally, this alteration was detected in a cohort of 29,906 healthy individuals who underwent multigene panel testing (Grzymski JJ et al. Nat Med, 2020 08;26:1235-1239). 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.
Fulgent Genetics, Fulgent Genetics	RCV001099061	SCV002784628	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-09-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001099061	SCV004844011	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 53 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 been reported in double heterozygous state with a known pathogenic LDLR variant in two related individuals affected with severe homozygous familial hypercholesterolemia, a phenotype expected of having two deleterious variants (PMID: 27919364). This variant has been identified in 4/223722 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.
CeGaT Center for Human Genetics Tuebingen	RCV004808741	SCV005432562	uncertain significance	not provided	2024-11-01	criteria provided, single submitter	clinical testing	PCSK9: PM2:Supporting, BP4
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum	RCV000508806	SCV000606679	pathogenic	Hypercholesterolemia, familial, 1		no assertion criteria provided	research