Submissions for variant NM_002225.5(IVD):c.358G>A (p.Gly120Arg) (rs142761835)

Total submissions: 7

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
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000153385	SCV000230190	pathogenic	not provided	2016-03-16	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.
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	2019-09-23	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 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. This variant disrupts the p.Gly123 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in affected individuals (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, Oman	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		criteria provided, single submitter	clinical testing