Submissions for variant NM_002225.5(IVD):c.596G>T (p.Gly199Val)

gnomAD frequency: 0.00002  dbSNP: rs121434285

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000432851	SCV000521033	pathogenic	not provided	2016-07-26	criteria provided, single submitter	clinical testing	The G202V missense variant in the IVD gene has been reported previously in association with isovaleric acidemia (IVA), using alternate nomenclature (G170V) (Vockley et al., 1991). Functional studies in E. coli suggest G202V has little detectable protein activity compared to wild type (Mohsen et al., 1998). The G202V variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G202V substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, Glycine 202 is located in the FAD binding domain of the isovaleryl-CoA dehydrogenase protein (Vockley et al., 1991). In summary, we interpret G202V to be a pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000984276	SCV003442813	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 202 of the IVD protein (p.Gly202Val). This variant is present in population databases (rs121434285, gnomAD 0.002%). This missense change has been observed in individuals with isovaleric acidemia (PMID: 9665741; Invitae). This variant is also known as c.596G>T (p.Gly170Val). ClinVar contains an entry for this variant (Variation ID: 3563). 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. Experimental studies have shown that this missense change affects IVD function (PMID: 9665741). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323350	SCV004029415	uncertain significance	not specified	2023-07-27	criteria provided, single submitter	clinical testing	Variant summary: IVD c.596G>T (p.Gly199Val) results in a non-conservative amino acid change located in the middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251480 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.596G>T has been reported in the literature in at least one compound heterozygous fibroblast cell line from an individual affected with Isovaleryl-CoA Dehydrogenase Deficiency (e.g., Vockley_1991, Mohsen_1998). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in an absence of detectable enzymatic activity, potentially due to protein misfolding (e.g., Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9665741, 2063866). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: two submitters classified the variant as a VUS, and one submitter classified it as pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV000984276	SCV004197995	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2024-03-05	criteria provided, single submitter	clinical testing
OMIM	RCV000003744	SCV000023909	pathogenic	Isovaleric acidemia, type I	1991-07-01	no assertion criteria provided	literature only
Counsyl	RCV000984276	SCV001132419	uncertain significance	Isovaleryl-CoA dehydrogenase deficiency	2017-09-13	no assertion criteria provided	clinical testing