ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.618del (p.Ile206fs)

dbSNP: rs781630355
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526058 SCV000631890 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ile209Metfs*40) in the IVD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IVD are known to be pathogenic (PMID: 16602101). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with IVD-related conditions. ClinVar contains an entry for this variant (Variation ID: 459930). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000599150 SCV000710512 pathogenic not provided 2020-10-27 criteria provided, single submitter clinical testing Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Illumina Laboratory Services, Illumina RCV000526058 SCV000915669 uncertain significance Isovaleryl-CoA dehydrogenase deficiency 2018-04-09 criteria provided, single submitter clinical testing The IVD c.627delT (p.Ile209MetfsTer40) variant results in a frameshift, and is predicted to result in premature termination of the protein. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.00005 in the European (non-Finnish) population from the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of frameshift variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for isovaleric acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000526058 SCV003929276 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-04-12 criteria provided, single submitter clinical testing Variant summary: IVD c.618delT (p.Ile206MetfsX40) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2.8e-05 in 251488 control chromosomes (gnomAD). c.618delT has been reported in the literature to be found in a cohort of newborns confirmed to have inborn errors of metabolism, however, no further details were provided (Adhikari_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Isovaleryl-CoA Dehydrogenase Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=2) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000526058 SCV004198002 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-10-16 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000526058 SCV004238253 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-06-27 criteria provided, single submitter clinical testing

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