Submissions for variant NM_000017.4(ACADS):c.1153G>T (p.Ala385Ser)

dbSNP: rs202124189

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000419832	SCV000517196	uncertain significance	not provided	2023-03-02	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: 32778825, 22241096)
Counsyl	RCV000675060	SCV000800519	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2017-05-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000675060	SCV000948668	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 385 of the ACADS protein (p.Ala385Ser). This variant is present in population databases (rs202124189, gnomAD 0.01%). This missense change has been observed in individuals with biochemical features of short-chain acyl-coenzyme A dehydrogenase deficiency (Invitae). ClinVar contains an entry for this variant (Variation ID: 379779). 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. This variant disrupts the p.Ala385 amino acid residue in ACADS. Other variant(s) that disrupt this residue have been observed in individuals with ACADS-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Genome-Nilou Lab	RCV000675060	SCV002033260	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004022322	SCV004916802	uncertain significance	Inborn genetic diseases	2024-02-27	criteria provided, single submitter	clinical testing	The c.1153G>T (p.A385S) alteration is located in exon 10 (coding exon 10) of the ACADS gene. This alteration results from a G to T substitution at nucleotide position 1153, causing the alanine (A) at amino acid position 385 to be replaced by a serine (S). Based on data from gnomAD, the T allele has an overall frequency of 0.002% (5/248180) total alleles studied. This alteration was detected in an individual with elevations in C4 acylcarnitines and ethylmalonic aciduria in combination with homozygous ACADS c.625G>A, a common variant that is not thought to be causative of short-chain acyl-CoA dehydrogenase deficiency (Pena, 2012). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.