ClinVar Miner

Submissions for variant NM_014384.2(ACAD8):c.958G>A (p.Ala320Thr) (rs200620279)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000414228 SCV000700401 uncertain significance not provided 2017-04-12 criteria provided, single submitter clinical testing
GeneDx RCV000414228 SCV000490392 pathogenic not provided 2016-01-06 criteria provided, single submitter clinical testing The A320T missense variant in the ACAD8 gene has been reported previously in a patient with isobutyryl-CoA dehydrogenase deficiency who was compound heterozygous for A320T and another variant in the ACAD8 gene (Pedersen et al., 2006). Expression studies found that A320T is associated with approximately 20% isobutyryl-CoA dehydrogenase enzyme activity compared to wild-type and that it affects proper isobutyryl-CoA dehydrogenase protein folding (Pedersen et al., 2006). The A320T variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The A320T variant is a non-conservative amino acid substitution, and it occurs at a position that is conserved across species. In summary, we interpret A320T to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000692863 SCV000914498 likely pathogenic Deficiency of isobutyryl-CoA dehydrogenase 2018-12-05 criteria provided, single submitter clinical testing The ACAD8 c.958G>A (p.Ala320Thr) missense variant has been reported in a compound heterozygous state in two individuals with isobutyryl-CoA dehydrogenase deficiency who were identified by elevated C4-carnitine levels through newborn screening (Pedersen et al. 2006; Oglesbee et al. 2007). This variant was absent from 415 controls but is reported at a frequency of 0.001563 in the European (Finnish) population of the Genome Aggregation Database. When overexpressed in Chang cells, the p.Ala320Thr variant displayed approximately 20% residual enzyme activity. Experiments in isolated mitochondria also showed the variant reduced isobutyryl-CoA dehydrogenase tetramer formation, suggesting disruption of protein folding (Pedersen et al. 2006). Based on the collective evidence, the p.Ala320Thr variant is classified as likely pathogenic for isobutyryl-CoA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000692863 SCV000820709 uncertain significance Deficiency of isobutyryl-CoA dehydrogenase 2018-03-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 320 of the ACAD8 protein (p.Ala320Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs200620279, ExAC 0.08%). This variant has been reported in combination with other ACAD8 variants in individuals affected with isobutyryl-CoA dehydrogenase deficiency (PMID: 16857760, 17304052). ClinVar contains an entry for this variant (Variation ID: 372297). Experimental studies have shown that this missense change retains a 20% of residual ACAD8 enzymatic activity (PMID: 16857760). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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