rs2229311
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_002225.5(IVD):c.149G>A(p.Arg50His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,824 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R50C) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IVD | NM_002225.5 | c.149G>A | p.Arg50His | missense_variant | 2/12 | ENST00000487418.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IVD | ENST00000487418.8 | c.149G>A | p.Arg50His | missense_variant | 2/12 | 1 | NM_002225.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251478Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135910
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461676Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12AN XY: 727158
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74328
ClinVar
Submissions by phenotype
Isovaleryl-CoA dehydrogenase deficiency Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the IVD protein (p.Arg53His). This variant is present in population databases (rs2229311, gnomAD 0.006%). This missense change has been observed in individual(s) with isovaleric acidemia (PMID: 15486829, 17027310, 19099814, 27904153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.149G>A (p.Arg21His). ClinVar contains an entry for this variant (Variation ID: 370843). 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. This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 10677295, 15486829, 17576084), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 28, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 19, 2023 | - - |
Inborn genetic diseases Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 2021 | The c.158G>A (p.R53H) alteration is located in exon 2 (coding exon 2) of the IVD gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/251478) total alleles studied. The highest observed frequency was 0.01% (2/34592) of Latino alleles. This alteration, also described as p.R21H in literature, has been reported in the homozygous state or compound heterozygous state with a second IVD alteration in several patients with isovaleric acidemia (Ensenauer, 2004; Lin, 2007; Couce, 2017; Li, 2019; Ibarra-González, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 09, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Sometimes reported as R21H or R50H using alternate nomenclature; This variant is associated with the following publications: (PMID: 25220015, 19099814, 15486829, 22960500, 33565069, 32778825, 32505769, 31442447, 27904153, 17027310, 31707166) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at