Submissions for variant NM_000017.4(ACADS):c.136C>T (p.Arg46Trp) (rs121908003)

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Total submissions: 5

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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	pathogenic	not provided	2017-06-30	criteria provided, single submitter	clinical testing	The R46W variant has previously been reported in association with short chain acyl-CoA dehydrogenase (SCAD) deficiency (Naito et al., 1990). Functional analysis of R46W, reported as R22W, found that it is associated with increased degregation, reduced tetramer formation, increased aggregation tendency, and increased chaperone retention (Corydon et al., 1998; Pedersen et al., 2003). Therefore, we interpret R46W to be a pathogenic variant.
Invitae	RCV000004029	SCV000940838	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2019-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with tryptophan at codon 46 of the ACADS protein (p.Arg46Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121908003, ExAC 0.05%). This variant has been observed in combination with another ACADS variant in individuals affected with SCAD deficiency (PMID: 28454995, 18523805, 1692038). This variant is also known as R22W in the literature. ClinVar contains an entry for this variant (Variation ID: 3825). Experimental studies have shown that this missense change disrupts ACADS protein folding and abrogates enzymatic activity (PMID: 9582344, 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.
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

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