rs148562777
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP5BS2
The NM_174936.4(PCSK9):c.1069C>T(p.Arg357Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000973 in 1,614,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R357H) has been classified as Uncertain significance.
Frequency
Consequence
NM_174936.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.1069C>T | p.Arg357Cys | missense_variant | 7/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.1069C>T | p.Arg357Cys | missense_variant | 7/12 | 1 | NM_174936.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000145 AC: 22AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000151 AC: 38AN: 251372Hom.: 0 AF XY: 0.000184 AC XY: 25AN XY: 135898
GnomAD4 exome AF: 0.0000924 AC: 135AN: 1461802Hom.: 0 Cov.: 35 AF XY: 0.0000949 AC XY: 69AN XY: 727214
GnomAD4 genome ? AF: 0.000144 AC: 22AN: 152340Hom.: 0 Cov.: 33 AF XY: 0.000188 AC XY: 14AN XY: 74488
ClinVar
Submissions by phenotype
Hypercholesterolemia, autosomal dominant, 3 Pathogenic:2Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 02, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 357 of the PCSK9 protein (p.Arg357Cys). This variant is present in population databases (rs148562777, gnomAD 0.04%). This missense change has been observed in individual(s) with hypercholesterolemia (PMID: 29127338, 30270359, 33418990). ClinVar contains an entry for this variant (Variation ID: 575758). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects PCSK9 function (PMID: 29127338). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | This missense variant replaces arginine with cysteine at codon 357 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An invitro functional study has shown that this variant causes higher binding affinity for LDLR and results in reduced LDL uptake activity compared to wildtype (PMID: 29127338). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 33418990, 34297352, Fairoozy 2018, dissertation, University College London). One of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33418990). This variant has been identified in 41/282766 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Arcensus | Feb 01, 2013 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of molecular diagnosis of dyslipidemias, Università egli studi di Napoli Federico II | May 24, 2021 | Gain of function according to functional studies PMID:29127338 - |
not provided Pathogenic:2Uncertain:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 07, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33258288, 30270359, 16211558, 29127338, 25904937) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PCSK9: PM1, PM5, PS3:Moderate, PS4:Moderate, PM2:Supporting, PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Feb 15, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
PCSK9-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 27, 2024 | The PCSK9 c.1069C>T variant is predicted to result in the amino acid substitution p.Arg357Cys. This variant was reported in individuals with hypercholesterolaemia (Di Taranto et al 2017. PubMed ID: 29127338; Meshkov A et al 2021. PubMed ID: 33418990). In vitro functional studies suggest this variant leads to a gain of function in the NARC1 protein that results in increased degradation of LDLR and consequently higher levels of LDL in the blood, which may present as familial hypercholesteremia (Di Taranto et al. 2017. PubMed ID: 29127338). This variant results in an amino acid change within the conserved catalytic site of the NARC1 protein (Allard et al. 2005. PubMed ID: 16211558; Di Taranto et al. 2017. PubMed ID: 29127338). A similar variant that results in the amino acid change p.Arg357His has also been reported in patients with hypercholesterolaemia (Allard et al. 2005. PubMed ID: 16211558). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD, which may be too common to be a primary cause of disease. At this time, the clinical significance of this variant is uncertain. - |
Hypobetalipoproteinemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Familial hypercholesterolemia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 27, 2023 | This missense variant replaces arginine with cysteine at codon 357 of the PCSK9 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An invitro functional study has shown that this variant causes higher binding affinity for LDLR and results in reduced LDL uptake activity compared to wildtype (PMID: 29127338). This variant has been reported in three individuals affected with familial hypercholesterolemia (PMID: 33418990, 34297352, Fairoozy 2018, dissertation, University College London). One of these individuals also carried a pathogenic variant in the same gene that could explain the observed phenotype (PMID: 33418990). This variant has been identified in 41/282766 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