Submissions for variant NM_174936.4(PCSK9):c.1547G>T (p.Gly516Val)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000497166	SCV000588685	uncertain significance	Hypercholesterolemia, familial, 1	2016-03-01	criteria provided, single submitter	research
Illumina Laboratory Services, Illumina	RCV001099460	SCV001255916	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001099461	SCV001255917	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	RCV001190153	SCV001357574	uncertain significance	Familial hypercholesterolemia	2019-08-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 516 of the PCSK9 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with probable hypercholesterolemia (PMID: 26802169) and in six unrelated South African individuals affected with familial hypercholesterolemia (Huijgen et al., 2017). This variant has been identified in 1/31398 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.
Fulgent Genetics, Fulgent Genetics	RCV001099460	SCV002785344	uncertain significance	Hypercholesterolemia, autosomal dominant, 3	2021-08-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235253	SCV003934239	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: PCSK9 c.1547G>T (p.Gly516Val) results in a non-conservative amino acid change located in the Proprotein convertase subtilisin/kexin type 9, C-terminal domain 1 (IPR041254) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31398 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1547G>T has been reported in the literature in individuals affected with Familial Hypercholesterolemia as well as in carriers (Wintjens_2016, Huijgen_2020, Diboun_2022). These reports do not provide unequivocal conclusions about association of the variant with Familial Hypercholesterolemia. At least two functional studies report this variant showed higher affinities for the LDLR than WT PCSK9 in transfected cells and in vitro studies confirm that PCSK9-G516V qualifies as a genuine GOF mutation (Huijgen_2020, Sarkar_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35910211, 33147992, 36187800, 26802169). Four ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.