ClinVar Miner

Submissions for variant NM_002225.4(IVD):c.149G>A (p.Arg50His) (rs2229311)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000411182 SCV000486257 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2016-04-28 criteria provided, single submitter clinical testing
Invitae RCV000411182 SCV000931264 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 53 of the IVD protein (p.Arg53His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs2229311, ExAC 0.009%). This variant has been observed in homozygous and compound heterozygous individuals affected with isovaleric acidemia (PMID: 19099814, 17027310, 27904153, 15486829). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. This variant is also known as c.149G>A (p.Arg21His) in the literature. ClinVar contains an entry for this variant (Variation ID: 370843). 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 and their clinical significance is uncertain. This variant disrupts the p.Arg53 amino acid residue in IVD. Other variants that disrupt this residue have been observed in affected individuals (PMID: 17576084, 15486829, 10677295), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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