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

dbSNP: rs781340220

Total submissions: 2

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.