Submissions for variant NM_000017.4(ACADS):c.815G>A (p.Arg272His)

gnomAD frequency: 0.00004  dbSNP: rs374726386

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185688	SCV000238609	likely pathogenic	not provided	2017-04-11	criteria provided, single submitter	clinical testing	The R272H variant waspreviously reported in a homozygous state in an individual with significant ethylmalonic aciduria andsignificantly elevated butyrylcarnitine in plasma (van Maldegem et al., 2006). This individual was alsohomozygous for the common G209S variant in the ACADS gene (van Maldegem et al., 2006). TheR272H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016;1000 Genomes Consortium et al., 2015; Exome Variant Server). The R272H variant is a conservativeamino acid substitution, which is not likely to impact secondary protein structure as these residuesshare similar properties. This substitution occurs at a position that is conserved across species. In silicoanalysis predicts this variant is probably damaging to the protein structure/function. Another missensevariant in the same residue (R272C) has been reported in the Human Gene Mutation Database inassociation with SCAD deficiency (Stenson et al., 2014), supporting the functional importance of thisregion of the protein. In summary, the R272H variant is likely pathogenic; however, the possibilitythat it is benign cannot be excluded.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000664591	SCV001398824	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-04-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the ACADS protein (p.Arg272His). This variant is present in population databases (rs374726386, gnomAD 0.01%). This missense change has been observed in individual(s) with biochemical features of SCAD deficiency (PMID: 16926354, 32710939). ClinVar contains an entry for this variant (Variation ID: 203556). 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 expected to disrupt ACADS protein function with a positive predictive value of 95%. This variant disrupts the p.Arg272 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27051597; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	RCV000664591	SCV002033250	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993871	SCV004813624	uncertain significance	not specified	2024-02-20	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.815G>A (p.Arg272His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal domain (IPR009075) 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 5.5e-05 in 1610504 control chromosomes (gnomAD). c.815G>A has been reported in the literature in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (examples: van Maldegem_2006, Lin_2020, Maguolo_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32710939, 32793418, 16926354). ClinVar contains an entry for this variant (Variation ID: 203556). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000664591	SCV005632327	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2024-03-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000664591	SCV000788580	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2017-10-03	no assertion criteria provided	clinical testing