ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.362C>T (p.Thr121Ile) (rs121434283)

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Total submissions: 7
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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)
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000003782 SCV000268484 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Invitae RCV000003782 SCV000630283 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-09-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 121 of the ACADM protein (p.Thr121Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs121434283, ExAC 0.001%). This variant has been reported to be the most common cause of MCAD deficiency in Saudi Arabia, although it has also been found in other populations. It has been found in the homozygous state or in combination with other known pathogenic variants in the ACADM gene (PMID: 11349232, 17273963, 20567907, 24966162, 25503862). ClinVar contains an entry for this variant (Variation ID: 3599). Experimental studies have shown that this missense change reduces the ACADM enzymatic activity (PMID: 11349232) and causes the out-of-frame skipping of exon 5 (PMID: 17273963). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000185674 SCV000884948 pathogenic not provided 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, Oman RCV000003782 SCV000891587 uncertain significance 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.
OMIM RCV000003782 SCV000023947 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2007-03-01 no assertion criteria provided literature only

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