Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000009777 | SCV004020847 | pathogenic | Deficiency of 2-methylbutyryl-CoA dehydrogenase | 2023-06-28 | criteria provided, single submitter | clinical testing | Variant summary: ACADSB c.1228G>A (p.Gly410Ser) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase C-terminal domain (IPR009075) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. This was confirmed via cDNA sequencing of a homozygous patient, which showed that the variant causes skipping of exon 10 (Andresen_2000). The variant allele was found at a frequency of 2.9e-05 in 237360 control chromosomes (gnomAD). c.1228G>A has been reported in the literature in a Pakistani family with two homozygous individuals affected with Deficiency of 2-methylbutyryl-CoA Dehydrogenase (Andresen_2000). These data indicate that the variant is likely to be associated with disease. Although the variant did not cause absence of the protein through nonsense mediated decay, fibroblasts from a homozygous patient showed less than 10% residual activity when compared to control fibroblasts (Andresen_2000). The following publication have been ascertained in the context of this evaluation (PMID: 11013134). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. |
| OMIM | RCV000009777 | SCV000029998 | pathogenic | Deficiency of 2-methylbutyryl-CoA dehydrogenase | 2000-11-01 | no assertion criteria provided | literature only |