Submissions for variant NM_000016.6(ACADM):c.92G>A (p.Arg31His)

gnomAD frequency: 0.00001  dbSNP: rs529894272

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001065937	SCV001230928	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-16	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 31 of the ACADM protein (p.Arg31His). This variant is present in population databases (rs529894272, gnomAD 0.03%). This missense change has been observed in individual(s) with medium chain acyl-CoA dehydrogenase deficiency (PMID: 24966162; Invitae). ClinVar contains an entry for this variant (Variation ID: 859753). 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 95%. Experimental studies have shown that this missense change affects ACADM function (PMID: 24966162). This variant disrupts the p.Arg31 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been observed in individuals with ACADM-related conditions (PMID: 33841490), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001732031	SCV001983393	uncertain significance	not specified	2021-09-21	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.92G>A (p.Arg31His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251416 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (4.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.92G>A has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Bentler_2016, Tucci_2021). These data indicate that the variant may be associated with disease. In a functional study, the variant was reported to have a C8-CoA oxidation activity of 40% compared to wild-type with similar temperature-sensitive decreases in activity compared to wild-type (Koster_2014). The authors described this as a mild biochemical phenotype in vitro. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Baylor Genetics	RCV001065937	SCV004212236	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-10-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001065937	SCV001460420	uncertain significance	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2020-09-16	no assertion criteria provided	clinical testing