Submissions for variant NM_000017.4(ACADS):c.2T>C (p.Met1Thr)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003226718	SCV003922834	likely pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-03-15	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.2T>C (p.Met1Thr) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of two in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 156242 control chromosomes. c.2T>C has been reported in the literature in individuals affected with Deficiency Of Butyryl-CoA Dehydrogenase. These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that no detectable SCAD protein in the two patients carrying this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, c.1A>G (p.Met1Val) was reported in ClinVar with conflicting interpretations of pathogenicity (likely pathogenic n=2, VUS n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003226718	SCV004354697	pathogenic	Deficiency of butyryl-CoA dehydrogenase	2023-06-06	criteria provided, single submitter	clinical testing	Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 2501121). Disruption of the initiator codon has been observed in individual(s) with short-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 18523805; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects the initiator methionine of the ACADS mRNA. The next in-frame methionine is located at codon 40. This variant disrupts a region of the ACADS protein in which other variant(s) (p.Arg23Trp) have been observed in individuals with ACADS-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.