Submissions for variant NM_000016.6(ACADM):c.134A>G (p.Gln45Arg)

gnomAD frequency: 0.00002  dbSNP: rs757434857

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000723521	SCV000331231	likely pathogenic	not provided	2017-07-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000333494	SCV000931696	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-11	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 45 of the ACADM protein (p.Gln45Arg). This variant is present in population databases (rs757434857, gnomAD 0.006%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18241067, 20434380, 22796001; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 281077). 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 ACADM protein function. Experimental studies have shown that this missense change affects ACADM function (PMID: 26947917). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000333494	SCV003922432	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-03-17	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.134A>G (p.Gln45Arg) results in a conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251266 control chromosomes (gnomAD). c.134A>G has been reported in the literature in the compound heterozygous state in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Nichols_2008, Purevsuren_2009, Rucklova_2021). These data indicate that the variant may be associated with disease. A publication reporting experimental evidence evaluating an impact on protein function found that the variant resulted in reduced protein expression, which was prone to misfolding and/or aggregation, and that the variant had 11% of normal activity (Hara_2016). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic, likely pathogenic, and VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV000333494	SCV004217278	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-11-30	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000333494	SCV005661609	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-06-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000333494	SCV000792455	uncertain significance	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2017-06-27	flagged submission	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751414	SCV005364259	pathogenic	ACADM-related disorder	2024-07-30	no assertion criteria provided	clinical testing	The ACADM c.134A>G variant is predicted to result in the amino acid substitution p.Gln45Arg. This variant has been reported with other ACADM variants in multiple individuals with biochemical features consistent with medium-chain acyl-CoA dehydrogenase deficiency (see for example, Nichols et al. 2008. PubMed ID: 18241067; Purevsuren et al. 2008. PubMed ID: 19064330; Table S2, Rücklová et al. 2021. PubMed ID: 34578803). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. An in vitro experimental study suggests this variant affects protein expression and MCAD enzyme activity (Hara et al. 2015. PubMed ID: 26947917). This variant is interpreted as pathogenic.