rs121909334
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong
The NM_007126.5(VCP):c.572G>C(p.Arg191Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R191Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_007126.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
VCP | NM_007126.5 | c.572G>C | p.Arg191Pro | missense_variant | 5/17 | ENST00000358901.11 | |
VCP | NM_001354927.2 | c.437G>C | p.Arg146Pro | missense_variant | 5/17 | ||
VCP | NM_001354928.2 | c.437G>C | p.Arg146Pro | missense_variant | 5/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
VCP | ENST00000358901.11 | c.572G>C | p.Arg191Pro | missense_variant | 5/17 | 1 | NM_007126.5 | P3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University | Mar 31, 2020 | - - |
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia;C5436279:Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 03, 2023 | 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: 873223). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 32579787, 32671691; Invitae). 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 arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 191 of the VCP protein (p.Arg191Pro). This variant disrupts the p.Arg191 amino acid residue in VCP. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15034582, 19237541, 21145000, 21984748, 22270372, 22900631). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at