Submissions for variant NM_000017.4(ACADS):c.1138C>T (p.Arg380Trp)

gnomAD frequency: 0.00004  dbSNP: rs28940875

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185699	SCV000238620	likely pathogenic	not provided	2023-01-13	criteria provided, single submitter	clinical testing	Functional studies found R380W is associated with no detectable ACADS enzyme activity (Corydon et al., 2001); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Previously reported as R356W due to the use of alternate nomenclature; This variant is associated with the following publications: (PMID: 18523805, 14595061, 21483766, 16906473, 29678161, 24485985, 11134486, 22424739, 19800078, 16546179, 16926354, 32253862, 31589614, 32710939, 36499071, 33726816)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004041	SCV000756744	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-11-18	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 380 of the ACADS protein (p.Arg380Trp). This variant is present in population databases (rs28940875, gnomAD 0.05%). This missense change has been observed in individuals with SCAD deficiency (PMID: 11134486, 14595061, 16906473, 16926354, 22424739, 24485985). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3837). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ACADS protein function. Experimental studies have shown that this missense change affects ACADS function (PMID: 18523805). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004041	SCV001440546	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2019-01-01	criteria provided, single submitter	clinical testing	This variant was identified as compound heterozygous.
Centre for Inherited Metabolic Diseases, Karolinska University Hospital	RCV000004041	SCV001547503	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-03-19	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000004041	SCV002033282	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
DASA	RCV000004041	SCV002073760	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-02-05	criteria provided, single submitter	clinical testing	The c.1138C>T;p.(Arg380Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3837; PMID: 29678161; 24485985; 22424739; 16926354; 11134486) - PS4. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 24485985) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28940875 – gnomAD 0.0003941%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg380Trp) was detected in trans with a pathogenic variant (PMID: 24485985; 22424739; 16926354) - PM3. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
MGZ Medical Genetics Center	RCV000004041	SCV002580934	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-06-27	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000004041	SCV002810482	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-08-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000004041	SCV003808371	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-05-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004041	SCV004121942	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-10-20	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.1138C>T (p.Arg380Trp) results in a non-conservative amino acid change in 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 9.3e-05 in 248232 control chromosomes (gnomAD). c.1138C>T has been reported in the literature in multiple individuals affected with short-chain acyl-CoA dehydrogenase (SCAD) deficiency (examples: Bok_2003, Edhager_2014, Navarrete_2019). These data indicate that the variant is very likely to be associated with disease. Multiple publications have reported experimental evidence that this variant changes the normal protein function (examples: Edhager_2014, Bok_2003). The following publications have been ascertained in the context of this evaluation (PMID: 24485985, 30626930, 18523805, 14595061). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000004041	SCV005051744	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-02-01	criteria provided, single submitter	curation
OMIM	RCV000004041	SCV000024207	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2001-01-01	no assertion criteria provided	literature only
Counsyl	RCV000004041	SCV000220689	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2018-10-16	no assertion criteria provided	clinical testing