Submissions for variant NM_002225.5(IVD):c.932C>T (p.Ala311Val)

gnomAD frequency: 0.00077  dbSNP: rs28940889

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000080003	SCV000233053	pathogenic	not provided	2014-08-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000080003	SCV000238934	pathogenic	not provided	2021-07-15	criteria provided, single submitter	clinical testing	Reported in association with isovaleric acidemia (IVA) and has been found in a homozygous or compound heterozygous state with another IVD pathogenic variant in approximately two-thirds of newborns with IVA diagnosed by newborn screening (Ensenauer et al., 2004); 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 (Ensenauer et al., 2004); Published functional studies demonstrate A314V results in reduced isovaleryl-CoA dehydrogenase activity compared to wild-type (Mohsen et al. 1998); This variant is associated with the following publications: (PMID: 26937393, 16602101, 27904153, 25087612, 22995991, 9665741, 15486829, 15337167, 22960500, 26018748, 31980526, 28631226, 29431110, 31707166, 34426522, 32778825, 27535533, 24077912)
Illumina Laboratory Services, 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	2022-03-02	criteria provided, single submitter	clinical testing
Invitae	RCV000003749	SCV000631895	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 314 of the IVD protein (p.Ala314Val). This variant is present in population databases (rs28940889, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with NBS or mild elevations of isovaleric acidemia-related metabolites and residual IVD enzyme activity (PMID: 15486829). 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 p.Ala282Val. ClinVar contains an entry for this variant (Variation ID: 100060). 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. Experimental studies have shown that this missense change affects IVD function (PMID: 9665741). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000003749	SCV001163388	pathogenic	Isovaleryl-CoA dehydrogenase deficiency		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000003749	SCV001194070	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2019-11-13	criteria provided, single submitter	clinical testing	NM_002225.3(IVD):c.941C>T(A314V, aka A311V) is classified as pathogenic in the context of isovaleric acidemia. Please note that individuals with the A314V variant may have a mild form of isovaleric acidemia or may be asymptomatic. Sources cited for classification include the following: PMID 15486829, 15337167 and 9665741. Classification of NM_002225.3(IVD):c.941C>T(A314V, aka A311V) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000003749	SCV001428919	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2018-01-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001266807	SCV001444986	pathogenic	Inborn genetic diseases	2021-05-27	criteria provided, single submitter	clinical testing	The c.941C>T (p.A314V) alteration is located in exon 9 (coding exon 9) of the IVD gene. This alteration results from a C to T substitution at nucleotide position 941, causing the alanine (A) at amino acid position 314 to be replaced by a valine (V). Based on data from the Genome Aggregation Database (gnomAD) database, the IVD c.941C>T alteration was observed in 0.07% (184/282758) of total alleles studied, with a frequency of 0.12% (156/129130) in the European (non-Finnish) subpopulation. This alteration (referred to as A282V in some publications) has been reported in the homozygous and compound heterozygous states in many individuals with isovaleric acidemia (IVA) (Ensenauer, 2004; Lambrecht, 2015; Mütze, 2021; Szymaska, 2020; Tangeraas, 2020). Most patients are reported to have mild elevation of isovalerylcarnitine, but are clinically asymptomatic (Ensenauer, 2004; Lambrecht, 2015; Mütze, 2021). A few patients have been reported with a mild symptomatic form of IVA (Mütze, 2021; Szymaska, 2020). The p.A314 amino acid is conserved in available vertebrate species. When expressed in E. coli, this alteration was shown to result in a less stable protein which was catalytically less efficient as compared to wild-type (Mohsen, 1998). Biochemical studies using lymphocytes and fibroblasts from patients homozygous for this alteration showed accumulation of isovalerylcarnitine in the cell medium, but at levels lower than patients with other known pathogenic variants (Ensenauer, 2004). This alteration has also been shown to have diminished thermal stability (Nasser, 2004). The p.A314V alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000080003	SCV001468012	pathogenic	not provided	2020-10-13	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000003749	SCV002023194	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-09-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003749	SCV003800904	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-01-21	criteria provided, single submitter	clinical testing	Variant summary: IVD c.932C>T (p.Ala311Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251360 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IVD causing Isovaleryl-CoA Dehydrogenase Deficiency (0.00064 vs 0.0022), allowing no conclusion about variant significance. c.932C>T has been reported in the literature in multiple individuals affected with a milder/subclinical presentation of Isovaleryl-CoA Dehydrogenase Deficiency/Isovaleric acidemia (IVA) (example, PMID: 27904153, 15486829, 9665741). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function in vitro (PMID: 9665741). The most pronounced variant effect results in <3% of normal catalytic efficiency per mole of flavin adenine dinucleotide (FAD) content and 19% of wild type Isovaleryl-CoA dehydrogenase (IVD) enzyme activity. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000080003	SCV003917366	pathogenic	not provided	2023-09-01	criteria provided, single submitter	clinical testing	IVD: PM3:Strong, PM1, PM2, PP4, PS3:Supporting
PreventionGenetics, part of Exact Sciences	RCV003952534	SCV004769221	pathogenic	IVD-related condition	2024-02-16	criteria provided, single submitter	clinical testing	The IVD c.941C>T variant is predicted to result in the amino acid substitution p.Ala314Val. This variant, which has also been described as 932C>T (A282V) in the literature, has been documented causative for isovaleric acidemia and has been reported to be associated with a more clinically mild phenotype or found in asymptomatic individuals identified by newborn screening (Mohsen et al. 1998. PubMed ID: 9665741; Ensenauer et al. 2004. PubMed ID: 15486829; Vockley and Ensenauer. 2006. PubMed ID: 16602101; Couce et al. 2017. PubMed ID: 27904153). In functional studies, the activity of the IVD enzyme with the p.Ala314Val substitution was reduced to <20% of wild-type (Mohsen et al. 1998. PubMed ID: 9665741). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic.
OMIM	RCV000003749	SCV000023914	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2004-12-01	no assertion criteria provided	literature only