Submissions for variant NM_000017.4(ACADS):c.814C>T (p.Arg272Cys)

gnomAD frequency: 0.00006  dbSNP: rs539219309

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000443456	SCV000511939	likely pathogenic	not provided	2023-02-09	criteria provided, single submitter	clinical testing	Not observed at 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: 18836889, 27938594, 27051597, 33895855)
Invitae	RCV000635334	SCV000756732	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-10-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the ACADS protein (p.Arg272Cys). This variant is present in population databases (rs539219309, gnomAD 0.008%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 27051597; Invitae). ClinVar contains an entry for this variant (Variation ID: 377422). 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 observed in individuals with ACADS-related conditions (PMID: 32710939), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000635334	SCV002033249	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV000635334	SCV002578128	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2022-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000635334	SCV004223696	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.814C>T (p.Arg272Cys) results in a non-conservative amino acid change to a highly conserved residue (HGMD) 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 3.2e-05 in 247630 control chromosomes (gnomAD). c.814C>T has been reported in the literature in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase (Tonin_2016, Huang_2016). These data indicate that the variant is likely to 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: 27051597, 33895855, 27938594). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as likely pathogenic (n=4) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl	RCV000635334	SCV001132115	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2019-01-24	no assertion criteria provided	clinical testing