ClinVar Miner

Submissions for variant NM_002225.3(IVD):c.941C>T (p.Ala314Val) (rs28940889)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000080003 SCV000233053 pathogenic not provided 2014-08-20 criteria provided, single submitter clinical testing
GeneDx RCV000080003 SCV000238934 pathogenic not provided 2018-03-29 criteria provided, single submitter clinical testing The A314V missense variant in the IVD gene has been reported previously in association with isovaleric acidemia (IVA) (Ensenauer et al., 2004). This variant has been found in a homozygous or compound heterozygous state with another IVD variant in approximately two-thirds of newborns with IVA diagnosed by newborn screening. Thus far, all of the newborns harboring A314V, including compound heterozygotes for this variant, have a mild biochemical phenotype and have remained asymptomatic with no or limited treatment. Based on the available evidence, we consider A314V to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000003749 SCV000390865 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-04-27 criteria provided, single submitter clinical testing The IVD c.941C>T (p.Ala314Val) missense variant, also known as p.Ala282Val, is well-described in the literature as a common variant associated with isovaleric acidemia (IVA). Across a selection of the available literature, the p.Ala314Val variant has been identified in a homozygous state in six patients and in a compound heterozygous state in nine patients (Mohsen et al. 1998; Ensenauer et al. 2004; Lambrecht et al. 2015). The patients all presented with a very mild or asymptomatic clinical phenotype. One of the homozygous individuals also presented with Angelmann syndrome (Lambrecht et al. 2015). The p.Ala314Val variant was absent from 100 controls and is reported at a frequency of 0.00118 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies in patient cells and E. coli demonstrated that the variant resulted in reduced enzyme activity compared to wild type, ranging from no activity to 19% activity (Mohsen et al. 1998; Ensenauer et al. 2004). The enzyme also exhibits diminished thermal stability (Nasser et al. 2004). Based on the evidence, the p.Ala314Val variant is classified as pathogenic for isovaleric acidemia with an associated mild clinical presentation. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000080003 SCV000511591 pathogenic not provided 2017-01-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003749 SCV000611275 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-05-18 criteria provided, single submitter clinical testing
Invitae RCV000003749 SCV000631895 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2018-02-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 314 of the IVD protein (p.Ala314Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs28940889, ExAC 0.1%). This variant is frequently detected in individuals identified from NBS or asymptomatic individuals with mild elevations of isovaleric acidemia-related metabolites and residual IVD enzyme activity (PMID: 15486829). It has been reported as homozygous or in combination with other IVD variants in individuals affected with isovaleric acidemia (PMID: 15486829, 9665741, 27904153). This variant is also known as p.Ala282Val in the literature. ClinVar contains an entry for this variant (Variation ID: 10060). Experimental studies have shown that this variant caused partial reduction of enzyme activity in vitro (PMID: 9665741). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003749 SCV000023914 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2004-12-01 no assertion criteria provided literature only
Counsyl RCV000003749 SCV000485182 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2016-01-07 no assertion criteria provided clinical testing

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