ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.148C>T (p.Arg50Cys)

dbSNP: rs34695403
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000003748 SCV000941046 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2024-01-04 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the IVD protein (p.Arg53Cys). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs34695403, gnomAD 0.003%). This missense change has been observed in individuals with isovaleric acidemia (PMID: 10677295, 31442447; Invitae). This variant is also known as 148C>T (Arg21Cys). ClinVar contains an entry for this variant (Variation ID: 3567). 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. Studies have shown that this missense change results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 2063866, 10677295). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000003748 SCV001163379 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000003748 SCV004122503 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-10-04 criteria provided, single submitter clinical testing Variant summary: IVD c.148C>T (p.Arg50Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and causes skipping of exon 2 (Vockley_2000). The variant allele was found at a frequency of 1.2e-05 in 251486 control chromosomes (gnomAD). c.148C>T has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (Vockley_2000, Li_2019). These data indicate that the variant may be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26990548, 22960500, 17001642, 31442447, 34394177, 10677295). Two 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 likely pathogenic.
OMIM RCV000003748 SCV000023913 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2000-02-01 no assertion criteria provided literature only
Natera, Inc. RCV000003748 SCV001460257 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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