rs569379713
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_174936.4(PCSK9):c.212C>T(p.Pro71Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P71P) has been classified as Likely benign.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.212C>T | p.Pro71Leu | missense_variant | 2/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.212C>T | p.Pro71Leu | missense_variant | 2/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000108 AC: 27AN: 250360Hom.: 0 AF XY: 0.000148 AC XY: 20AN XY: 135440
GnomAD4 exome AF: 0.0000499 AC: 73AN: 1461752Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58AN XY: 727186
GnomAD4 genome ? AF: 0.0000328 AC: 5AN: 152324Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4AN XY: 74484
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | May 11, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 01, 2023 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 13, 2023 | - - |
Uncertain significance, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Aug 28, 2017 | 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. - |
Hypercholesterolemia, familial, 1 Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratorium voor Moleculaire Diagnostiek Experimentele Vasculaire Geneeskunde, Academisch Medisch Centrum | - | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Phosphorus, Inc. | Jan 15, 2022 | 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 03, 2020 | 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. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 22, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at