Submissions for variant NM_000017.4(ACADS):c.136C>T (p.Arg46Trp)

gnomAD frequency: 0.00008  dbSNP: rs121908003

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000004029	SCV000220171	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2014-03-16	criteria provided, single submitter	literature only
GeneDx	RCV000185706	SCV000238627	likely pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	Published functional studies demonstrate increased protein degradation, reduced tetramer formation, increased aggregation tendency, and increased chaperone retention (PMID: 9582344, 14506246); 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: 14506246, 28516284, 18523805, 1692038, 22424739, 18676165, 28454995, 34426522, 31589614, 31980526, 32778825, 33239584, 38103157, 38137468, 38882225, 9582344, 34493867)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004029	SCV000940838	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 46 of the ACADS protein (p.Arg46Trp). This variant is present in population databases (rs121908003, gnomAD 0.08%). This missense change has been observed in individuals with SCAD deficiency (PMID: 1692038, 18523805, 28454995). This variant is also known as R22W. ClinVar contains an entry for this variant (Variation ID: 3825). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACADS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ACADS function (PMID: 9582344, 14506246). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000004029	SCV002792455	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-04-05	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004029	SCV003808394	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-06-03	criteria provided, single submitter	clinical testing
3billion	RCV000004029	SCV003841754	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-02-23	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 14506246, 9582344). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.94; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000003825). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 1692038, 28454995). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000004029	SCV004805177	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-03-17	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004029	SCV004813527	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.136C>T (p.Arg46Trp) results in a non-conservative amino acid change located in the acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251496 control chromosomes (gnomAD). c.136C>T has been reported in the literature as a biallelic genotype in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (e.g. Naito_1990, Pedersen_2008, Alfares_2017). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (Corydon_1998, Pedersen_2003). The results showed that the variant primarily existed as an insoluble protein, likely due to protein misfolding, and resulted in <10% of normal activity. The following publications have been ascertained in the context of this evaluation (PMID: 28454995, 9582344, 1692038, 18523805, 14506246). ClinVar contains an entry for this variant (Variation ID: 3825). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV004965258	SCV005524114	likely pathogenic	Inborn genetic diseases	2024-08-30	criteria provided, single submitter	clinical testing	The c.136C>T (p.R46W) alteration is located in exon 2 (coding exon 2) of the ACADS gene. This alteration results from a C to T substitution at nucleotide position 136, causing the arginine (R) at amino acid position 46 to be replaced by a tryptophan (W). Based on data from gnomAD, the T allele has an overall frequency of 0.015% (42/282878) total alleles studied. The highest observed frequency was 0.078% (24/30616) of South Asian alleles. This variant has been identified in the homozygous state and/or in conjunction with another ACADS variant in individuals with short-chain acyl-CoA dehydrogenase deficiency; in at least one instance, the variants were identified in trans (Naito, 1990; Alfares, 2017). This amino acid position is well conserved in available vertebrate species. In multiple assays testing ACADS function, this variant showed functionally abnormal results (Corydon, 1998; Pedersen, 2003). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	RCV000004029	SCV005873759	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-08-11	criteria provided, single submitter	clinical testing
OMIM	RCV000004029	SCV000024195	pathogenic	Deficiency of butyryl-CoA dehydrogenase	1989-11-01	no assertion criteria provided	literature only
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000004029	SCV001133031	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2019-09-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003398440	SCV004120760	pathogenic	ACADS-related disorder	2024-08-19	no assertion criteria provided	clinical testing	The ACADS c.136C>T variant is predicted to result in the amino acid substitution p.Arg46Trp. This variant was previously referred to as R22W in the literature. This variant has been reported in the homozygous or compound heterozygous state in patients with short chain acyl-CoA-dehydrogenase deficiency (Corydon et al. 1998. PubMed ID: 9582344; Alfares et al. 2017. PubMed ID: 28454995; Messina M et al. 2020. PubMed ID: 33239584). In experimental studies, the p.Arg46Trp substitution has been shown to result in decreased enzyme activity as well as affecting protein folding, increased protein aggregation, and more rapid degradation than wild-type (Corydon et al. 1998. PubMed ID: 9582344; Pedersen et al. 2003. PubMed ID: 14506246). The c.136C>T variant has been reported at a maximum allele frequency of ~0.08% in a large population database, indicating it is rare in the general population. In summary, we classify this variant as pathogenic.