rs864309501
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PP2PP3_ModeratePP5_Very_Strong
The NM_007126.5(VCP):c.553G>A(p.Glu185Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E185D) has been classified as Uncertain significance.
Frequency
Consequence
NM_007126.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCP | NM_007126.5 | c.553G>A | p.Glu185Lys | missense_variant | 5/17 | ENST00000358901.11 | |
VCP | NM_001354927.2 | c.418G>A | p.Glu140Lys | missense_variant | 5/17 | ||
VCP | NM_001354928.2 | c.418G>A | p.Glu140Lys | missense_variant | 5/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCP | ENST00000358901.11 | c.553G>A | p.Glu185Lys | missense_variant | 5/17 | 1 | NM_007126.5 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461886Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2Y Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2014 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 24, 2020 | The p.E185K variant (also known as c.553G>A), located in coding exon 5 of the VCP gene, results from a G to A substitution at nucleotide position 553. The glutamic acid at codon 185 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this variant is predicted to be deleterious by in silico analysis. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported to segregate with disease in one family and in-vitro functional studies showed that it resulted in impaired autophagic function (Gonzalez MA et al. Brain, 2014 Nov;137:2897-902). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects VCP function (PMID: 25125609). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt VCP protein function. ClinVar contains an entry for this variant (Variation ID: 218305). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease (PMID: 25125609). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 185 of the VCP protein (p.Glu185Lys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at