ClinVar Miner

Submissions for variant NM_174936.4(PCSK9):c.212C>T (p.Pro71Leu)

dbSNP: rs569379713
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000539746 SCV000644869 likely benign Hypercholesterolemia, autosomal dominant, 3 2024-01-08 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001182723 SCV001348278 uncertain significance Familial hypercholesterolemia 2023-06-22 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 71 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 individuals affected with familial hypercholesterolemia (PMID: 26374825, 36499307) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 27/250360 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.
Phosphorus, Inc. RCV001823731 SCV002073425 uncertain significance not specified 2022-01-15 criteria provided, single submitter clinical testing This missense variant results in an amino acid substitution of proline with leucine at codon 71 of the PCSK9 gene. The variant has an entry in ClinVar (440711) NM_174936.4 (PCSK9): c.212C>T (p.Pro71Leu) and has occurred in GnomAD with a total MAF of 0.0106% and highest MAF of 0.0650% in the South Asian population. This position is not conserved. In silico functional algorithms disagreed, with PolyPhen calling it benign, and SIFT deleterious, but no functional studies were performed to confirm these predictions. The variant has previously been identified in an individual with a coronary artery disease who suffered from a stroke (PMID: 27920219) and in an individual affected with hypercholesterolemia where the variant was considered a gain-of-function mutation (PMID: 26374825). Further evidence is needed to establish whether this variant contributes to disease formation. The variant has therefore been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV002420289 SCV002726124 uncertain significance Cardiovascular phenotype 2020-01-03 criteria provided, single submitter clinical testing The p.P71L variant (also known as c.212C>T), located in coding exon 2 of the PCSK9 gene, results from a C to T substitution at nucleotide position 212. The proline at codon 71 is replaced by leucine, an amino acid with similar properties. This variant was reported in six individuals from a familial hypercholesterolemia cohort; however, clinical details were limited and possible familial relationships were unknown (Hopkins PN et al. Circ Cardiovasc Genet, 2015 Dec;8:823-31). This amino acid position is poorly 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.
New York Genome Center RCV000539746 SCV003925117 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2022-05-11 criteria provided, single submitter clinical testing The c.212C>T variant in PCSK9 has previously been reported in individuals with clinical features of familial hypercholesterolemia, coronary artery disease (CAD) and stroke [PMID: 26374825, 27920219, 34526433] and it has been deposited in ClinVar [ClinVar ID: 440711] as a Variant of Uncertain Significance. The c.212C>T variant is observed in 34 alleles (0.0063 % minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.212C>T variant in PCSK9 is located in exon 2 of this 12-exon gene and is predicted to replace a weakly conserved proline amino acid with leucine at position 71 of this 692-amino-acid protein. In silico tools predict the p.(Pro71Leu) variant tobe benign [(CADD v1.6 = 15.72, REVEL = 0.079)]; however, there are no functional studies to support or refute these predictions. Based on the available evidence, the c.212C>T p.(Pro71Leu) missense variant identified in the PCSK9 gene is reported as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000786182 SCV004222374 likely benign not provided 2023-06-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV000539746 SCV004844088 uncertain significance Hypercholesterolemia, autosomal dominant, 3 2023-12-01 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 71 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 individuals affected with familial hypercholesterolemia (PMID: 26374825, 36499307) and in an individual affected with acute coronary syndrome (PMID: 34526433). This variant has been identified in 27/250360 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.
Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum RCV000508916 SCV000606683 pathogenic Hypercholesterolemia, familial, 1 no assertion criteria provided research
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786182 SCV000924890 uncertain significance not provided 2017-08-28 no assertion criteria provided provider interpretation p.Pro71Leu (c.212C>T) in the PCSK9 gene (NM_174936.3) - variant of uncertain significance, probably benign Given the unconvincing case data and its prevalence in the general population, we consider this variant a variant of uncertain significance and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). However, it may be suitable for family studies (testing only related, affected individuals) to determine its effect on cholesterol levels in this family. Gain of function variants in PCSK9 cause autosomal dominant hypercholesterolemia. This variant is not reported in ClinVar. It has been reported in a total of 6 individuals (not including our patient). This variant was reported in 6 individuals from the Netherlands with a total cholesterol of ~220 mg/dL and LDL cholesterol of ~115g mg/dL (Hopkins et al 2015). It is not clear whether any or all of these individuals were related. It is notable that 11/164 patients in this study had a variant in both PCSK9 and LDLR (pathogenicity of these variants has not been included in this review). An editorial by McNutt & Ahmad in 2015 questions whether this variant is truly pathogenic given that these patients had total cholesterol and LDL-C levels that are lower than typical for familial hypercholesterolemia (FH). Family studies may be useful to determine whether this variant has a synergistic effect with the LDLR variant. Per the test report, "Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on he potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0")." The variant was reported online in 26 of 122,596 individuals in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Ashkenazi, Latino descent. Specifically, the variant was observed in 20 of 15,389 individuals of South Asian descent (MAF=0.065%), 2 of 8,623 individuals of East Asian descent, 1 out of 16,787 individuals of Latino descent and 3 of 55,386 individuals of European descent. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease.

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