Submissions for variant NM_002225.5(IVD):c.149G>A (p.Arg50His)

gnomAD frequency: 0.00001  dbSNP: rs2229311

Total submissions: 6

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	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the IVD protein (p.Arg53His). This variant is present in population databases (rs2229311, gnomAD 0.006%). This missense change has been observed in individual(s) with isovaleric acidemia (PMID: 15486829, 17027310, 19099814, 27904153). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.149G>A (p.Arg21His). ClinVar contains an entry for this variant (Variation ID: 370843). 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.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been observed in individuals with IVD-related conditions (PMID: 10677295, 15486829, 17576084), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000411182	SCV001440727	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001848730	SCV002104326	pathogenic	not provided	2022-03-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Sometimes reported as R21H or R50H using alternate nomenclature; This variant is associated with the following publications: (PMID: 25220015, 19099814, 15486829, 22960500, 33565069, 32778825, 32505769, 31442447, 27904153, 17027310, 31707166)
Ambry Genetics	RCV002523859	SCV003560072	likely pathogenic	Inborn genetic diseases	2021-08-27	criteria provided, single submitter	clinical testing	The c.158G>A (p.R53H) alteration is located in exon 2 (coding exon 2) of the IVD gene. This alteration results from a G to A substitution at nucleotide position 158, causing the arginine (R) at amino acid position 53 to be replaced by a histidine (H). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (7/251478) total alleles studied. The highest observed frequency was 0.01% (2/34592) of Latino alleles. This alteration, also described as p.R21H in literature, has been reported in the homozygous state or compound heterozygous state with a second IVD alteration in several patients with isovaleric acidemia (Ensenauer, 2004; Lin, 2007; Couce, 2017; Li, 2019; Ibarra-Gonz&aacute;lez, 2020). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Baylor Genetics	RCV000411182	SCV004198018	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-08-19	criteria provided, single submitter	clinical testing