Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000211542 | SCV000268460 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2015-02-20 | criteria provided, single submitter | clinical testing | |
| Gene |
RCV000421774 | SCV000521112 | likely pathogenic | not provided | 2016-09-29 | criteria provided, single submitter | clinical testing | The R294T missense variant in the ACADM gene has been reported in a patient with MCAD deficiency who also harbored the common pathogenic K329E variant on the opposite ACADM allele (in trans) (McKinney et al. 2004). R294T was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R294T variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, we interpret the R294T variant to be likely pathogenic. |
| Fulgent Genetics, |
RCV000211542 | SCV000894143 | likely pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000211542 | SCV002247402 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2023-10-16 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 294 of the ACADM protein (p.Arg294Thr). This variant is present in population databases (rs779759347, gnomAD 0.0009%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 15171998, 30675864). ClinVar contains an entry for this variant (Variation ID: 226075). 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. For these reasons, this variant has been classified as Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000211542 | SCV004020531 | likely pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2023-06-15 | criteria provided, single submitter | clinical testing | Variant summary: ACADM c.881G>C (p.Arg294Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR009075) 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 4e-06 in 250574 control chromosomes (i.e. 1 allele in gnomAD v2.1). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.881G>C has been reported in the literature in at least 3 individuals diagnosed with Medium Chain Acyl-CoA Dehydrogenase Deficiency (MCADD) (e.g. McKinney_2004, Adhikari_2020, Li_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, nearby missense changes have been reported in affected individuals (HGMD), indicating a functional importance for the protein region. The following publications have been ascertained in the context of this evaluation (PMID: 32778825, 36068006, 15171998, 30675864). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=2)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Baylor Genetics | RCV000211542 | SCV004217411 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2024-03-25 | criteria provided, single submitter | clinical testing |