ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.1399C>G (rs772677312)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Cardiovascular Research Group,Instituto Nacional de Saude Doutor Ricardo Jorge RCV000256342 SCV000323068 likely pathogenic Familial hypercholesterolemia 1 2016-03-01 criteria provided, single submitter research 0/190 non-FH alleles (portuguese normolipidemic individuals)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781701 SCV000919964 uncertain significance not specified 2020-11-16 criteria provided, single submitter clinical testing Variant summary: PCSK9 c.1399C>G (p.Pro467Ala) results in a non-conservative amino acid change located in the proprotein convertase subtlisin/kexin type 9, C-terminal domain (IPR041254) of 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 2.8e-05 in 251378 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1399C>G has been reported in the literature in at-least one individual affected with Familial Hypercholesterolemia in whom two novel putative gain of function variants, namely, this one and p.Ala62Asp were identified (Alves_2015). This individual was reported as having no mutation in the LDL receptor (LDLR) or apolipoprotein B100 (APOB) genes. The variant was paternally inherited but the specific lipid profile was not reported. In contrast, at-least one co-occurrence with another pathogenic variant has been observed at our laboratory (LDLR c.1897C>T, p.Arg633Cys), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 56% of normal LDLR cell surface expression and reduced LDL uptake (Alves_2015). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely pathogenic, n=1; VUS, n=4). Some submitters provide overlapping evidence utilized in the context of this evaluation. Based on the equivocal evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000811853 SCV000952141 uncertain significance Familial hypercholesterolemia 3 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces proline with alanine at codon 467 of the PCSK9 protein (p.Pro467Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. This variant is present in population databases (rs772677312, ExAC 0.006%). This variant has been observed in individuals clinical features of familial hypercholesterolemia (PMID: 26541928, Invitae). ClinVar contains an entry for this variant (Variation ID: 265944). Experimental studies have shown that this missense change decreases LDLR cell surface localization and LDL uptake (PMID: 26541928). 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.
Illumina Clinical Services Laboratory,Illumina RCV001095906 SCV001252083 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.
Illumina Clinical Services Laboratory,Illumina RCV000811853 SCV001252084 uncertain significance Familial hypercholesterolemia 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.
Color Health, Inc RCV001191122 SCV001358821 uncertain significance Familial hypercholesterolemia 2019-06-13 criteria provided, single submitter clinical testing
Laboratory of Molecular Genetics,National Medical Research Center for Therapy and Preventive Medicine RCV001191122 SCV001482450 likely pathogenic Familial hypercholesterolemia criteria provided, single submitter research
CSER _CC_NCGL, University of Washington RCV000256342 SCV000503526 uncertain significance Familial hypercholesterolemia 1 2016-08-01 no assertion criteria provided research Found in patient having exome sequencing for an unrelated indication. No known history of hyperlipidemia.

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