Submissions for variant NM_000016.6(ACADM):c.1205G>A (p.Gly402Asp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002619245	SCV003496317	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 402 of the ACADM protein (p.Gly402Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 20434380; Invitae). ClinVar contains an entry for this variant (Variation ID: 2180420). 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 expected to disrupt ACADM protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003324075	SCV004030116	uncertain significance	not specified	2023-07-19	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.1205G>A (p.Gly402Asp) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, C-terminal (IPR009075) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250290 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1205G>A has been reported in the literature in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency and in the context of newborn screening (Ventura_2014, Smith_2010). These data do not allow any conclusion about variant significance. 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: 20434380, 23829193). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.