ClinVar Miner

Submissions for variant NM_002225.5(IVD):c.287-2A>G

dbSNP: rs781340220
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Neuberg Centre For Genomic Medicine, NCGM RCV001823529 SCV002073034 likely pathogenic Isovaleryl-CoA dehydrogenase deficiency criteria provided, single submitter clinical testing The splice acceptor variant c.287-2A>G in IVD (NM_002225.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.287-2A>G variant is observed in 3/30,616 (0.0098%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant affects an invariant splice nucelotide and is predicted to cause protien truncation. In silico tools predict a damaging effect. For these reasons, this variant has been classified as Likely Pathogenic
Invitae RCV001823529 SCV003336789 pathogenic Isovaleryl-CoA dehydrogenase deficiency 2023-11-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the IVD gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in IVD are known to be pathogenic (PMID: 16602101). This variant is present in population databases (rs781340220, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with isovaleric acidemia (Invitae). ClinVar contains an entry for this variant (Variation ID: 1339075). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

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