Submissions for variant NM_002225.5(IVD):c.109G>A (p.Asp37Asn)

dbSNP: rs2141289961

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001939420	SCV002231147	pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2021-10-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the IVD protein in which other variant(s) (p.Arg53His) have been determined to be pathogenic (PMID: 2063866, 10677295, 31442447; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Studies have shown that this variant results in skipping of exon 2, but is expected to preserve the integrity of the reading-frame (PMID: 10677295). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has been observed in individual(s) with IVD-related conditions (PMID: 9665741). This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with asparagine at codon 40 of the IVD protein (p.Asp40Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product.
Baylor Genetics	RCV001939420	SCV004198017	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2023-08-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001939420	SCV005422705	likely pathogenic	Isovaleryl-CoA dehydrogenase deficiency	2024-10-18	criteria provided, single submitter	clinical testing	Variant summary: IVD c.109G>A (p.Asp37Asn) also known as c.118G>A (p.Asp40Asn)results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. At least one publication reports experimental evidence that this variant affects mRNA splicing (internal_testing, Vockley_2000). The variant was absent in 245820 control chromosomes. c.109G>A has been reported in the literature in individuals affected with Isovaleryl-CoA Dehydrogenase Deficiency (Mohsen_1998). These report(s) do not provide unequivocal conclusions about association of the variant with Isovaleryl-CoA Dehydrogenase Deficiency. At least one publication reports experimental evidence evaluating an impact on protein function. This variant showed no detectable enzyme activity (Mohsen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 9665741, 10677295). ClinVar contains an entry for this variant (Variation ID: 1454153). Based on the evidence outlined above, the variant was classified as likely pathogenic.