ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.618del (p.Ile206fs) (rs781630355)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000599150 SCV000710512 pathogenic not provided 2018-01-24 criteria provided, single submitter clinical testing The c.627delT variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.627delT variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.627delT variant causes a frameshift starting with codon Isoleucine 209, changes this amino acid to a Methionine residue and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Ile209MetfsX40. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic.
Illumina Clinical Services Laboratory,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.
Invitae RCV000526058 SCV000631890 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2017-07-17 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. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with IVD-related disease. Loss-of-function variants in IVD are known to be pathogenic (PMID: 16602101). For these reasons, this variant has been classified as Pathogenic.

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