Submissions for variant NM_000016.6(ACADM):c.600-18G>A

gnomAD frequency: 0.00051  dbSNP: rs370523609

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211531	SCV000268471	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2015-02-20	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224275	SCV000280805	pathogenic	not provided	2015-03-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211531	SCV000754920	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 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 may result in an absent or disrupted protein product. This variant is present in population databases (rs370523609, gnomAD 0.2%). This variant has been observed in individual(s) with mild medium chain acyl-coenzyme A dehydrogenase (MCAD) deficiency on biochemical testing (PMID: 20434380, 26223887, 27308838, 27477829). 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: 226084). Studies have shown that this variant results in aberrant splicing and introduces a premature termination codon (PMID: 26223887). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000211531	SCV000893475	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2022-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224275	SCV001133288	likely pathogenic	not provided	2019-10-03	criteria provided, single submitter	clinical testing	The gain of a new splice site is predicted. Nucleotide conservation is uninformative. Occurs in multiple cases with a lone recessive pathogenic variant in the same gene. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Myriad Genetics, Inc.	RCV000211531	SCV001194138	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2019-12-20	criteria provided, single submitter	clinical testing	NM_000016.4(ACADM):c.600-18G>A is classified as likely pathogenic in the context of medium chain acyl-CoA dehydrogenase deficiency and is associated with a variable presentation, ranging from clinically asymptomatic to mild. Sources cited for classification include the following: PMID 31012112, 25255367, 20434380, 27477829, 26223887, 27308838 and 30626930. Classification of NM_000016.4(ACADM):c.600-18G>A is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211531	SCV001365621	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2020-03-31	criteria provided, single submitter	clinical testing	The c.612-18G>A (also known as c.600-18G>A, NM_000016.4) variant in ACADM has been reported in at least 8 individuals affected with mild medium-chain acyl-CoA dehydrogenase (MCAD) deficiency in the compound heterozygous state (variant in trans in at least 3 of these cases was the common c.985A > G (p.K329E); Smith 2010, Grunert 2015, Narravula 2017) . Additionally, the c.612-18G>A variant segregated with disease in 1 affected family member (Grunert 2015). This variant has also been reported in ClinVar (variation ID 226084). It has been identified in 0.2% (24/10364) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). In vivo and in vitro functional assays provide evidence that this variant lead to partial missplicing of the ACADM pre-mRNA and thereby affected protein function (Grunert 2015). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. ACMG/AMP Criteria applied: PM3_strong, PS3_Moderate.
GeneDx	RCV000224275	SCV001894773	pathogenic	not provided	2022-08-17	criteria provided, single submitter	clinical testing	Published functional studies suggest this variant leads to partial mis-splicing of the ACADM pre-mRNA (Grunert et al., 2015); This variant is associated with the following publications: (PMID: 22630369, 20434380, 27308838, 27477829, 26223887, 31012112, 30626930, 34426522, 32778825)
Revvity Omics, Revvity	RCV000211531	SCV002023974	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2019-10-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211531	SCV002511469	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-12-14	criteria provided, single submitter	clinical testing	Variant summary: Variant summary: ACADM c.600-18G>A alters a non-conserved 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 or weakens a cryptic 5' donor site, while two predict the variant creates a novel, cryptic 3' acceptor site, by introducing a novel AG upstream of the authentic 3' splice site AG. At least one publication reports experimental evidence demonstrating that this variant creates a cryptic 3' acceptor site that competes with the original 3' splice site, thus resulting in a partial splicing defect (Grunert_2015). The variant allele was found at a frequency of 0.00025 in 251270 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (0.00025 vs 0.0054), allowing no conclusion about variant significance. The variant, c.600-18G>A has been reported in the literature in multiple compound heterozygous individuals (who also carried a second pathogenic variant), detected during newborn screening in mostly clinically asymptomatic individuals as a biochemical phenotype (e.g. Touw_2012, Grunert_2015, Jager_2019), or in some cases in individuals with a reportedly milder form of Medium Chain Acyl-CoA Dehydrogenase Deficiency (e.g. Smith_2010). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant might represent a hypomorphic allele with variable penetrance, therefore it was classified as pathogenic for a milder disease phenotype.
Ambry Genetics	RCV002517448	SCV003694671	pathogenic	Inborn genetic diseases	2022-06-10	criteria provided, single submitter	clinical testing	The c.600-18G>A intronic alteration consists of a G to A substitution 18 nucleotides before coding exon 8 in the ACADM gene. This variant has been identified in apparently unaffected homozygous individuals in our laboratory (Ambry internal data). This alteration has been reported in the compound heterozygote states in individuals with medium chain acyl CoA dehydrogenase deficiency (Grünert, 2015; Navarrete, 2019; Smith, 2010; Touw, 2012). This nucleotide position is poorly conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). RNA studies have demonstrated that this alteration results in an incomplete splice defect (Grünert, 2015). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics	RCV000211531	SCV004212136	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-30	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000211531	SCV004807401	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-26	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000211531	SCV005052031	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-02-01	criteria provided, single submitter	curation
PreventionGenetics, part of Exact Sciences	RCV004751371	SCV005351635	likely pathogenic	ACADM-related disorder	2024-07-26	no assertion criteria provided	clinical testing	The ACADM c.600-18G>A variant is predicted to interfere with splicing. This variant has been registered in ClinVar as Pathogenic/Likely Pathogenic (www.ncbi.nlm.nih.gov/clinvar/variation/226084/). It is predicted to create a novel splice acceptor site 16 nucleotides upstream of the nearby canonical splice acceptor site (Alamut Visual v2.11). Functional studies indicated this variant led to partial abnormal splicing (Grünert et al. 2015. PubMed ID: 26223887). This variant has also been reported to be associated with medium chain acyl-CoA dehydrogenase deficiency (MCADD) (e.g., Grünert et al. 2015. PubMed ID: 26223887; Narravula et al. 2017. PubMed ID: 27308838) although it is not clear whether this variant is associated with a clinical phenotype (Smith et al. 2010. PubMed ID: 20434380; Grünert et al. 2015. PubMed ID: 26223887; Jager et al. 2019. PubMed ID: 31012112; Navarrete et al. 2019. PubMed ID: 30626930, Table S2). Based on these observations, we classify this variant as likely pathogenic.