Submissions for variant NM_000017.4(ACADS):c.1156C>T (p.Arg386Cys)

gnomAD frequency: 0.00003  dbSNP: rs537072819

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185703	SCV000238624	uncertain significance	not provided	2020-07-20	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 16906473, 32447334, 18836889, 33391346)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635335	SCV000756735	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-12-09	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 386 of the ACADS protein (p.Arg386Cys). This variant is present in population databases (rs537072819, gnomAD 0.02%). This missense change has been observed in individuals with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 16906473; Invitae). This variant is also known as Arg362Cys. ClinVar contains an entry for this variant (Variation ID: 203566). 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. 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	RCV000635335	SCV002033276	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000635335	SCV003822457	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2022-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317139	SCV004020720	uncertain significance	not specified	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.1156C>T (p.Arg386Cys) results in a non-conservative amino acid change located in the 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 5.6e-05 in 248252 control chromosomes (gnomAD, v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1156C>T has been reported in the literature as a biallelic compound heterozygous genotype in several individuals affected with features of short-chain acyl-CoA dehydrogenase (SCAD) deficiency/Deficiency Of Butyryl-CoA Dehydrogenase (e.g., Geregersen_2008, Wang_2020, Maguolo_2020, Jiang_2020). In some individuals, it was reported in trans with the commonly reported ACADS susceptibility allele c.625G>A (p.Gly209Ser), which is classified as benign/likely benign in the ClinVar database (Merinero_2006). 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: 18836889, 33391346, 32793418, 16906473, 32447334). Five ClinVar submitters (evaluation after 2014) have reported the variant with conflicting assessments: four submitters classified the variant as uncertain significance, and one submitter classified it as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl	RCV000635335	SCV001132319	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2016-08-29	no assertion criteria provided	clinical testing