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

gnomAD frequency: 0.00006  dbSNP: rs368469075

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185694	SCV000238615	pathogenic	not provided	2022-04-07	criteria provided, single submitter	clinical testing	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); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12872838, 18523805, 31813752, 23798014, 22241096, 18951053, 14506246)
Illumina Laboratory Services, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411694	SCV000952058	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 365 of the ACADS protein (p.Gln365His). This variant is present in population databases (rs368469075, gnomAD 0.01%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 12872838, 31813752; Invitae). This variant is also known as Gln341His. ClinVar contains an entry for this variant (Variation ID: 203560). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACADS protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADS function (PMID: 14506246). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Genome-Nilou Lab	RCV000411694	SCV002033257	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000411694	SCV003808383	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-03-29	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000411694	SCV005632332	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-06-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000411694	SCV005875339	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-12-15	criteria provided, single submitter	clinical testing	The ACADS c.1095G>T; p.Gln365His variant (rs368469075) is reported in the literature in individuals affected with deficiency of short-chain Acyl-CoA dehydrogenase (Jethva 2008, Pendersen 2008, Pena 2012, Sadat 2020, Seidel 2003, Waisbren 2013). This variant is also reported in ClinVar (Variation ID: 203560). This variant is found in the general population with an overall allele frequency of 0.004% (11/278,764 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.947). In vitro functional analyses demonstrated folding defects and difficulties for the variant protein to form a mature tetrameric enzyme (Pendersen 2003, Seidel 2003). Based on available information, this variant is considered to be pathogenic. References: Jethva R et al. Clinical outcomes of infants with short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD) detected by newborn screening. Mol Genet Metab. 2008 Dec;95(4):241-2. PMID: 18951053. Pedersen CB et al. Misfolding, degradation, and aggregation of variant proteins. The molecular pathogenesis of short chain acyl-CoA dehydrogenase (SCAD) deficiency. J Biol Chem. 2003 Nov 28;278(48):47449-58. PMID: 14506246. Pedersen CB et al. The ACADS gene variation spectrum in 114 patients with short-chain acyl-CoA dehydrogenase (SCAD) deficiency is dominated by missense variations leading to protein misfolding at the cellular level. Hum Genet. 2008 Aug;124(1):43-56. PMID: 18523805. Pena L et al. Follow-up of patients with short-chain acyl-CoA dehydrogenase and isobutyryl-CoA dehydrogenase deficiencies identified through newborn screening: one center's experience. Genet Med. 2012 Mar;14(3):342-7. PMID: 22241096. Sadat R et al. Increased parental anxiety and a benign clinical course: Infants identified with short-chain acyl-CoA dehydrogenase deficiency and isobutyryl-CoA dehydrogenase deficiency through newborn screening in Georgia. Mol Genet Metab. 2020 Jan;129(1):20-25. PMID: 31813752. Seidel J et al. Recurrent vomiting and ethylmalonic aciduria associated with rare mutations of the short-chain acyl-CoA dehydrogenase gene. J Inherit Metab Dis. 2003;26(1):37-42. PMID: 12872838. Waisbren SE et al. Neuropsychological outcomes in fatty acid oxidation disorders: 85 cases detected by newborn screening. Dev Disabil Res Rev. 2013;17(3):260-8. PMID: 23798014.
Counsyl	RCV000411694	SCV000486661	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2016-07-21	no assertion criteria provided	clinical testing