ClinVar Miner

Submissions for variant NM_000016.6(ACADM):c.946-6T>G

dbSNP: rs765793260
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674990 SCV000800411 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-06-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000674990 SCV001420435 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2023-12-29 criteria provided, single submitter clinical testing This sequence change falls in intron 10 of the ACADM gene. It does not directly change the encoded amino acid sequence of the ACADM protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 41 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs765793260, gnomAD 0.07%). This variant has been observed in individual(s) with MCAD deficiency (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: 558685). Studies have shown that this variant results in the activation of a cryptic splice site in exon 11 (PMID: 22542437). This variant disrupts the p.Met328 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23028790, 24966162; Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674990 SCV002600500 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2022-10-14 criteria provided, single submitter clinical testing Variant summary: ACADM c.946-6T>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 acceptor site. Four predict the variant creates a cryptic 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-05 in 249872 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (8e-05 vs 0.0054), allowing no conclusion about variant significance. c.946-6T>G has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Oerton_2011, Adhikari_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000674990 SCV003822452 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2021-08-10 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV000674990 SCV004047231 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency criteria provided, single submitter clinical testing The splice variant c.946-6T>G in ACADM gene has been reported previously in homozygous/ compound heterozygous state in patients affected with MCAD deficiency, in at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant (Andresen BS et al). The c.946-6T>G variant is reported with the allele frequency of 0.008004% in gnomAD Exome and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/Likely pathogenic. Experimental studies have shown that this variant disrupts mRNA splicing (Andresen BS et al). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics RCV000674990 SCV004213221 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2024-03-04 criteria provided, single submitter clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center RCV000674990 SCV004806052 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2024-03-25 criteria provided, single submitter clinical testing
Natera, Inc. RCV000674990 SCV002092858 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-08-21 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.