Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000016.6(ACADM):c.-6_6delGCCAACATGGCAinsACCCCGAGTG(p.Met1fs) variant causes a frameshift, start lost change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
ACADM (HGNC:89): (acyl-CoA dehydrogenase medium chain) This gene encodes the medium-chain specific (C4 to C12 straight chain) acyl-Coenzyme A dehydrogenase. The homotetramer enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. Defects in this gene cause medium-chain acyl-CoA dehydrogenase deficiency, a disease characterized by hepatic dysfunction, fasting hypoglycemia, and encephalopathy, which can result in infantile death. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
Verdict is Pathogenic. Variant got 20 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 243 pathogenic variants in the truncated region.
PS1
Another start lost variant in NM_000016.6 (ACADM) was described as [Likely_pathogenic] in ClinVar as 555765
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-75724782-GCCAACATGGCA-ACCCCGAGTG is Pathogenic according to our data. Variant chr1-75724782-GCCAACATGGCA-ACCCCGAGTG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 966945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Medium-chain acyl-coenzyme A dehydrogenase deficiency Pathogenic:2
Oct 11, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the ACADM protein in which other variant(s) (p.Arg29Leu) have been determined to be pathogenic (PMID: 20434380; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 966945). Disruption of the initiator codon has been observed in individual(s) with medium chain acyl-CoA dehydrogenase deficiency (PMID: 23028790, 30675864). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the ACADM mRNA. The next in-frame methionine is located at codon 87. -
May 12, 2021
Revvity Omics, Revvity
Significance: Likely pathogenic
Review Status: criteria provided, single submitter