Submissions for variant NM_002225.5(IVD):c.707C>T (p.Thr236Ile)

gnomAD frequency: 0.00010  dbSNP: rs146861563

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000275647	SCV000330834	likely pathogenic	not provided	2022-08-09	criteria provided, single submitter	clinical testing	Identified in asymptomatic individuals with positive newborn screening for isovaleric acidemia who were also heterozygous for a second variant in the IVD gene (Mtze U et al., 2021; D'Annibale OM et al., 2021); Published functional studies found this variant is associated with significantly reduced enzyme activity (D'Annibale OM et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as c.707 C>T (p.(T207I)); This variant is associated with the following publications: (PMID: 33496032, 34535384)
Counsyl	RCV000674322	SCV000799641	uncertain significance	Isovaleryl-CoA dehydrogenase deficiency	2018-04-30	criteria provided, single submitter	clinical testing
Invitae	RCV000674322	SCV001416609	uncertain significance	Isovaleryl-CoA dehydrogenase deficiency	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with isoleucine at codon 239 of the IVD protein (p.Thr239Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs146861563, ExAC 0.006%). This missense change has been observed in individual(s) with a positive newborn screening result for IVD-related disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 280881). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000674322	SCV002819569	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-05-10	criteria provided, single submitter	clinical testing	Variant summary: IVD c.707C>T (p.Thr236Ile) 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 3.2e-05 in 251480 control chromosomes. c.707C>T has been reported in the literature as a homozygous and heterozygous genotype in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency identified through Newborn screening (D'Annibale_2021, Molema_2018 and Mutze_2021). 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 indicating it to have stable IVDH protein but no enzyme activity (D'Annibale_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34535384, 30159853, 33496032). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and two classified it as VUS and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000674322	SCV004198014	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-09-01	criteria provided, single submitter	clinical testing