ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.358G>A (p.Gly120Arg)

gnomAD frequency: 0.00013  dbSNP: rs142761835
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169054 SCV000220214 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2014-04-04 criteria provided, single submitter literature only
Eurofins Ntd Llc (ga) RCV000153385 SCV000230190 pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing
GeneDx RCV000153385 SCV000321786 pathogenic not provided 2022-05-09 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as p.(G91R) or p.(G120R); This variant is associated with the following publications: (PMID: 25087612, 15486829, 22350545, 32778825, 28535199, 28631226, 27904153, 22004070, 31442447)
Fulgent Genetics, Fulgent Genetics RCV000169054 SCV000611202 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000169054 SCV000631885 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 123 of the IVD protein (p.Gly123Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with isovaleric acidemia (PMID: 22004070, 22350545, 27904153; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.358G>A (p.Gly91Arg). ClinVar contains an entry for this variant (Variation ID: 167199). 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.Gly123 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 15486829), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University RCV000169054 SCV000891669 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-12-30 criteria provided, single submitter clinical testing
Baylor Genetics RCV000169054 SCV001163382 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2022-05-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169054 SCV003922863 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-03-30 criteria provided, single submitter clinical testing Variant summary: IVD c.358G>A (p.Gly120Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251468 control chromosomes (gnomAD). c.358G>A (also known as c.367G>A, p.G123R) has been reported in the literature in multiple homozygous individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Carling_2018 and Dercksen_2012). At least one publication reports experimental evidence evaluating an impact on protein function. IVD enzyme activity from 10 homozygous individuals were below the quantification level (LOQ) of the validated assay (Dercksen_2012). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences RCV003416000 SCV004114400 pathogenic IVD-related disorder 2023-09-05 criteria provided, single submitter clinical testing The IVD c.367G>A variant is predicted to result in the amino acid substitution p.Gly123Arg. This variant (also referred to in the literature as c.358G>A or p.Gly91Arg) has been reported with a second IVD variant or in the homozygous state in a number of individuals with isovaleric acidemia (Vatanavicharn et al. 2011. PubMed ID: 22004070; Dercksen et al. 2012. PubMed ID: 22350545; Couce et al. 2017. PubMed ID: 27904153; Carling et al. 2018. PubMed ID: 28631226). In fibroblasts from patients described by Derckesen et al. (2012), isovaleryl-CoA dehydrogenase activity was undetectable and protein levels were markedly reduced. We have also observed this variant internally in a number of presumably affected individuals. Based on these observations, we classify this variant as pathogenic.
Natera, Inc. RCV000169054 SCV002094394 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-08-18 no assertion criteria provided clinical testing

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