Submissions for variant NM_000016.6(ACADM):c.362C>T (p.Thr121Ile)

gnomAD frequency: 0.00001  dbSNP: rs121434283

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000185674	SCV000238594	pathogenic	not provided	2021-06-22	criteria provided, single submitter	clinical testing	Functional studies demonstrated the variant resulted in skipping of exon 5 and premature termination and decreased medium chain acyl-CoA dehydrogenase activity compared to wild type (Nielsen et al., 2007); This variant is associated with the following publications: (PMID: 27535533, 31130284, 29268767, 24966162, 20567907, 17273963, 25503862, 11349232, 25525159)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000003782	SCV000630283	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 121 of the ACADM protein (p.Thr121Ile). This variant is present in population databases (rs121434283, gnomAD 0.004%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Saudi ancestry (PMID: 20567907). ClinVar contains an entry for this variant (Variation ID: 3599). 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 not expected to disrupt ACADM protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 11349232). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000003782	SCV000884948	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2018-04-05	criteria provided, single submitter	clinical testing	The ACADM c.362C>T; p.Thr121Ile variant (rs121434283), also known as T96I, has been described in the homozygous and compound heterozygous state in individuals affected with medium-chain acyl-coenzyme A dehydrogenase(MCAD) deficiency (Al-Hassnan 2010, Andresen 2001, Liang 2015, Nielsen 2007). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 3599) and is observed in the general population at a low overall frequency of 0.001% (3/246224 alleles) in the Genome Aggregation Database. Functional analyses of this variant demonstrate reduced enzymatic activity and skipping of exon 5 (Andresen 2001, Nielsen 2007). Based on available information, this variant is considered pathogenic. References: Al-Hassnan Z et al. Medium-chain acyl-CoA dehydrogenase deficiency in Saudi Arabia: incidence, genotype, and preventive implications. J Inherit Metab Dis. 2010 Dec;33 Suppl 3:S263-7. Andresen B et al. Medium-chain acyl-CoA dehydrogenase (MCAD) mutations identified by MS/MS-based prospective screening of newborns differ from those observed in patients with clinical symptoms: identification and characterization of a new, prevalent mutation that results in mild MCAD deficiency. Am J Hum Genet. 2001 Jun;68(6):1408-18. Liang C et al. First case report of medium-chain acyl-coenzyme A dehydrogenase deficiency in China. J Pediatr Endocrinol Metab. 2015 May;28(5-6):681-4. Nielsen K et al. Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007 Mar;80(3):416-32.
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000003782	SCV000891587	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2017-12-30	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000003782	SCV001623094	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2021-04-16	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.362C>T (p.Thr121Ile) results in a non-conservative amino acid change located in the Acyl-CoA dehydrogenase/oxidase, N-terminal domain (IPR013786) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, at least one publication reports experimental evidence that this variant affects mRNA splicing and displays a high level of exon 5 skipping which leads to a premature termination codon in exon 6 (Nielsen_2007). The variant allele was found at a frequency of 1.2e-05 in 251932 control chromosomes (gnomAD and publication data). c.362C>T has been reported in the literature in the compound heterozygous and homozygous state in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_2001, Nielseri_2007, Nichols_2008, Al-Hassnan_2010, Tangeraas_2020). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in reducing ACADM enzymatic activity (Andresen_2001). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and pathogenic (n=4). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV000003782	SCV003808360	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000003782	SCV004210704	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-02-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924799	SCV004742376	pathogenic	ACADM-related disorder	2024-02-14	criteria provided, single submitter	clinical testing	The ACADM c.362C>T variant is predicted to result in the amino acid substitution p.Thr121Ile. This variant has been reported in the homozygous and compound heterozygous states in multiple individuals with medium chain acyl-CoA dehydrogenase deficiency (see for example, Table 1, Andresen et al. 2001. PubMed ID: 11349232; Table 1, Liang et al. 2015. PubMed ID: 25503862; Table 1, Wen et al. 2022. PubMed ID: 35199448). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD and it has been described as a founder variant in Saudi Arabia (Al-Hassnan et al. 2010. PubMed ID: 20567907). This variant is interpreted as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000003782	SCV004804964	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-17	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000003782	SCV004847519	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2022-08-26	criteria provided, single submitter	clinical testing	The p.Thr121Ile variant in ACADM has been reported in >20 individuals with MCAD deficiency (Nielsen 2007 PMID: 17273963, Nichols 2008 PMID: 18241067, Al-Hassnan 2010 PMID: 20567907). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. A study found that the p.Thr121Ile variant causes exon 5 skipping and a premature termination codon in exon 6 as well as decreased levels of mRNA in patient cells (Nielsen 2007 PMID: 17273963). An additional study showed that this variant reduces ACADM enzymatic activity (Andresen 2001 PMID: 11349232). This variant has also been reported in ClinVar (Variation ID 3599). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive MCAD deficiency. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_M, PP3, PM2_P.
OMIM	RCV000003782	SCV000023947	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2007-03-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000003782	SCV002092821	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2017-05-03	no assertion criteria provided	clinical testing