15-40418174-C-G
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_002225.5(IVD):āc.1183C>Gā(p.Arg395Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000867 in 1,614,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R395Q) has been classified as Likely pathogenic.
Frequency
Consequence
NM_002225.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.1183C>G | p.Arg395Gly | missense_variant | 12/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.1183C>G | p.Arg395Gly | missense_variant | 12/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251400Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135884
GnomAD4 exome AF: 0.00000889 AC: 13AN: 1461872Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727236
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2023 | 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. This variant disrupts the p.Arg398 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22960500, 24516753). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 94052). This missense change has been observed in individual(s) with clinical features of isovaleric acidemia (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs398123681, gnomAD 0.002%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 398 of the IVD protein (p.Arg398Gly). - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 21, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at