rs786204613
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_002225.5(IVD):βc.1179delβ(p.Leu394PhefsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000062 in 1,614,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ).
Frequency
Genomes: π 0.000046 ( 0 hom., cov: 32)
Exomes π: 0.0000021 ( 0 hom. )
Consequence
IVD
NM_002225.5 frameshift
NM_002225.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.14
Genes affected
IVD (HGNC:6186): (isovaleryl-CoA dehydrogenase) Isovaleryl-CoA dehydrogenase (IVD) is a mitochondrial matrix enzyme that catalyzes the third step in leucine catabolism. The genetic deficiency of IVD results in an accumulation of isovaleric acid, which is toxic to the central nervous system and leads to isovaleric acidemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
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Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 13 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 15-40418167-CT-C is Pathogenic according to our data. Variant chr15-40418167-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.1179del | p.Leu394PhefsTer9 | frameshift_variant | 12/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.1179del | p.Leu394PhefsTer9 | frameshift_variant | 12/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251376Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135868
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461882Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 727240
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GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 30, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Leu397Phefs*9) in the IVD gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the IVD protein. This variant is present in population databases (rs753807321, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with IVA (PMID: 2063866). ClinVar contains an entry for this variant (Variation ID: 188993). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects IVD function (PMID: 10713113). This variant disrupts a region of the IVD protein in which other variant(s) (p.Glu411Lys) have been observed in individuals with IVD-related conditions (PMID: 22960500). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Feb 05, 2023 | PVS1, PS3, PM2, PM3, PP4 - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 14, 2016 | - - |
Isovaleric acidemia, type III Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 1991 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at