Submissions for variant NM_000017.4(ACADS):c.1195C>T (p.Arg399Trp)

dbSNP: rs375931905

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001308609	SCV001498068	uncertain significance	Deficiency of butyryl-CoA dehydrogenase	2022-12-14	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 1010893). This missense change has been observed in individuals with ACADS-related conditions (PMID: 32710939; Invitae). This variant is present in population databases (rs375931905, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 399 of the ACADS protein (p.Arg399Trp).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331110	SCV004037658	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: ACADS c.1195C>T (p.Arg399Trp) 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 4.1e-06 in 245740 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1195C>T has been reported in the literature in individuals affected with short- and very-long-chain-acyl-CoA dehydrogenase deficiencies (SCADD/VLCADD) (examples: Gong_2022, Tan_2021, and Lin_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Deficiency Of Butyryl-CoA Dehydrogenase. 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: 36207829, 32710939, 34394177). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Neonatal Disease Screening Center, Medical Genetics Center, Huaihua City Maternal and Child Health Care Hospital	RCV001308609	SCV004800870	pathogenic	Deficiency of butyryl-CoA dehydrogenase		no assertion criteria provided	clinical testing	PM2_P+PM3_VS+PP3+PP4