ClinVar Miner

Submissions for variant NM_002225.3(IVD):c.367G>A (p.Gly123Arg) (rs142761835)

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Total submissions: 6
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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
Department of Genetics,Sultan Qaboos University Hospital, Oman RCV000169054 SCV000891669 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-12-30 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000153385 SCV000230190 pathogenic not provided 2016-03-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000169054 SCV000611202 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-05-18 criteria provided, single submitter clinical testing
GeneDx RCV000153385 SCV000321786 pathogenic not provided 2017-09-01 criteria provided, single submitter clinical testing The G123R variant has previously been reported in association with isovaleric acidemia in several unrelated families of South African descent; affected individuals were homozygous for G123R and all patients were found to have undetectable residual isovaleryl-CoA dehydrogenase activity in fibroblasts (Dercksen et al., 2012). The G123R variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The G123R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position where amino acids with similar properties to Glycine are tolerated across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret G123R to be a pathogenic variant.
Invitae RCV000169054 SCV000631885 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2018-06-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 123 of the IVD protein (p.Gly123Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs142761835, ExAC 0.01%). This variant has been observed to segregate with isovaleric acidemia in two families (PMID: 22350545) and it has been reported as homozygous and in combination with another IVD variant in multiple individuals affected with IVA (PMID: 22350545, 27904153, 22004070, Invitae). This variant is also known as c.358G>A (p.Gly91Arg) in the literature.  ClinVar contains an entry for this variant (Variation ID: 167199). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Another missense substitution at this codon (p.Gly123Glu) has been reported in an individual affected with IVA (PMID: 15486829). For these reasons, this variant has been classified as Pathogenic.

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