Submissions for variant NM_002225.5(IVD):c.149G>C (p.Arg50Pro)

dbSNP: rs2229311

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169289	SCV000220605	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2014-08-19	criteria provided, single submitter	literature only
Fulgent Genetics, Fulgent Genetics	RCV000169289	SCV000893369	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2021-09-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000169289	SCV001163380	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2024-03-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001090731	SCV001246420	pathogenic	not provided	2018-04-01	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV001090731	SCV001251800	likely pathogenic	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV000169289	SCV001578737	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2020-09-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with proline at codon 53 of the IVD protein (p.Arg53Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs2229311, ExAC 0.02%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 27904153, 26018748, 9665741). This variant is also known as p.Arg21Pro in the literature. ClinVar contains an entry for this variant (Variation ID: 188922). This variant has been reported to affect IVD protein function (PMID: 9665741). This variant disrupts the p.Arg53 amino acid residue in IVD. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 110677295). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169289	SCV004100218	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-09-27	criteria provided, single submitter	clinical testing	Variant summary: IVD c.149G>C (p.Arg50Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251478 control chromosomes (gnomAD). c.149G>C has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (examples: Mohsen_1998, Ensenauer_2004, and Couce_2017). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 27904153, 15486829, 9665741). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003927565	SCV004740574	pathogenic	IVD-related disorder	2024-01-31	criteria provided, single submitter	clinical testing	The IVD c.158G>C variant is predicted to result in the amino acid substitution p.Arg53Pro. This variant, alternately described in the literature as Arg21Pro or c.149G>C, p.Arg50Pro, has been recurrently reported in patients with isovaleric acidemia and has been reported to impact protein function (Mohsen et al. 1998. PubMed ID: 9665741; Ensenauer et al. 2004. PubMed ID: 15486829; Sakamoto et al. 2015. PubMed ID: 26018748; Couce et al. 2016. PubMed ID: 27904153; D'Annibale et al. 2021. PubMed ID: 34535384; Mütze et al. 2021. PubMed ID: 33496032). Different substitutions of the same amino acid (p.Arg53Cys, p.Arg53His, p.Arg53Leu) have also been reported in isovaleric acidemia patients (Ensenauer et al. 2004. PubMed ID: 15486829; Lee et al. 2007. PubMed ID: 17576084; Li et al. 2019. PubMed ID: 31442447). This variant is reported in 0.0087% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic.
Natera, Inc.	RCV000169289	SCV002094382	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2017-03-17	no assertion criteria provided	clinical testing