Submissions for variant NM_000016.6(ACADM):c.158G>A (p.Arg53His)

gnomAD frequency: 0.00002  dbSNP: rs754938068

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211492	SCV000268450	uncertain significance	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2015-02-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211492	SCV001584378	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 53 of the ACADM protein (p.Arg53His). This variant is present in population databases (rs754938068, gnomAD 0.01%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 22630369, 31033143; Invitae). ClinVar contains an entry for this variant (Variation ID: 226066). 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 not expected to disrupt ACADM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). This variant disrupts the p.Arg53 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8102510, 15832312, 16737882, 20434380, 22796001, 24623196). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001753639	SCV001986126	uncertain significance	not provided	2021-05-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 31012112, 22630369, 31033143, 33841490)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211492	SCV004100069	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-09-22	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.158G>A (p.Arg53His) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251346 control chromosomes (gnomAD). c.158G>A has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (examples: Touw_2012, Li_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same residue (p.Arg53Cys) has been classified pathogenic in ClinVar (CV ID 92258). The following publications have been ascertained in the context of this evaluation (PMID: 31012112, 31033143, 22630369). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=1) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000211492	SCV004213210	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-07-02	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000211492	SCV004807355	uncertain significance	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-26	criteria provided, single submitter	clinical testing