ClinVar Miner

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

dbSNP: rs2229311
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Total submissions: 9
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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 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

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