ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.1199A>G (p.Tyr400Cys) (rs773560012)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000412119 SCV000486959 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency 2016-09-13 criteria provided, single submitter clinical testing
Baylor Genetics RCV000412119 SCV001163392 pathogenic Isovaleryl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing
Invitae RCV000412119 SCV001379719 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2020-05-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 403 of the IVD protein (p.Tyr403Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs773560012, ExAC 0.02%). This variant has been observed in individual(s) with isovaleric acidemia (PMID: 17027310, 20519759, 26018748). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Y371C in the literature. ClinVar contains an entry for this variant (Variation ID: 371390). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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