rs1553135406
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_174936.4(PCSK9):c.85del(p.Arg29ValfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A28A) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
PCSK9
NM_174936.4 frameshift
NM_174936.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.328
Genes affected
PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 53 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-55039919-GC-G is Pathogenic according to our data. Variant chr1-55039919-GC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496566.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PCSK9 | NM_174936.4 | c.85del | p.Arg29ValfsTer15 | frameshift_variant | 1/12 | ENST00000302118.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PCSK9 | ENST00000302118.5 | c.85del | p.Arg29ValfsTer15 | frameshift_variant | 1/12 | 1 | NM_174936.4 | P2 | |
PCSK9 | ENST00000710286.1 | c.442del | p.Arg148ValfsTer15 | frameshift_variant | 1/12 | A2 | |||
PCSK9 | ENST00000673913.2 | c.85del | p.Arg29ValfsTer15 | frameshift_variant, NMD_transcript_variant | 1/12 | ||||
PCSK9 | ENST00000673726.1 | c.85del | p.Arg29ValfsTer15 | frameshift_variant, NMD_transcript_variant | 1/6 |
Frequencies
GnomAD3 genomes ? Cov.: 34
GnomAD3 genomes
?
Cov.:
34
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1415904Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 700006
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1415904
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31
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0
AN XY:
700006
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 34
GnomAD4 genome
?
Cov.:
34
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypercholesterolemia, familial, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Iberoamerican FH Network | Mar 01, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 29, 2021 | Variant summary: PCSK9 c.85delC (p.Arg29ValfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for Hyporcholesterolemia but not for Hypercholesterolemia. The variant was absent in 175998 control chromosomes. To our knowledge, no occurrence of c.85delC in individuals affected with Familial Hypercholesterolemia and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Hyporcholesterolemia may associate with other symptoms (PMID 20626336). However, this variant is likely to confer protection against coronary artery disease due to its LDLC reducing effect (PMID 24507774). Based on the evidence outlined above, the variant was classified as VUS. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at