ClinVar Miner

Submissions for variant NM_000017.4(ACADS):c.1095G>T (p.Gln365His) (rs368469075)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185694 SCV000238615 pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing The Q365H variant has previously been reported in association with short chain acyl-CoAdehydrogenase (SCAD) deficiency (Seidel et al., 2003). Functional analysis of Q365H found that it is associated with reduced tetramer formation, increased aggregation tendency, and increased chaperone retention compared to wild-type, similar to other pathogenic variants in the ACADS gene (Seidel et al., 2003; Pedersen et al., 2008). Therefore, we interpret Q365H to be a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000411694 SCV000914567 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2019-01-10 criteria provided, single submitter clinical testing The ACADS c.1095G>T (p.Gln365His) missense variant has been reported in two studies in which it is found in a compound heterozygous state with another missense variant in two probands with short-chain acyl-coA dehydrogenase (SCAD) deficiency (Seidel et al. 2003; Pedersen et al. 2008). The p.Gln365His variant was absent from 100 control alleles and is reported at a frequency of 0.000128 in the African population of the Genome Aggregation Database. Functional studies in vitro revealed that the p.Gln365His variant was found to translate and import into mitochondria efficiently but had a decreased ability to form the mature tetrameric enzyme leading to misfolding, and a severe increased tendency to form aggregates especially at an elevated temperature (Seidel et al. 2003; Pedersen et al. 2008). Based on the evidence, the p.Gln365His variant is classified as likely pathogenic for short-chain acyl-coA dehydrogenase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000411694 SCV000952058 uncertain significance Deficiency of butyryl-CoA dehydrogenase 2020-07-12 criteria provided, single submitter clinical testing This sequence change replaces glutamine with histidine at codon 365 of the ACADS protein (p.Gln365His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present in population databases (rs368469075, ExAC 0.01%). This variant has been observed in an individual affected with SCAD deficiency (PMID: 12872838). This variant is also known as Gln341His in the literature. ClinVar contains an entry for this variant (Variation ID: 203560). Experimental studies have shown that this missense change causes a defect in protein folding (PMID: 14506246). 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.
Counsyl RCV000411694 SCV000486661 likely pathogenic Deficiency of butyryl-CoA dehydrogenase 2016-07-21 no assertion criteria provided clinical testing

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