ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.1052C>T (p.Thr351Ile) (rs766140986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185667 SCV000238586 likely pathogenic not provided 2018-04-18 criteria provided, single submitter clinical testing The T351I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. A mother and her child were found to harbor the T351I variant and the K329E pathogenic variant (reported using alternate nomenclature). The mother was diagnosed with medium chain acyl-CoA dehydrogenase (MCAD) deficiency biochemically after her children had a positive newborn screen for this condition. The mother is reported to have a mild phenotype, and experienced minor episodes of hypogylcemia as a child and adolescent. The child is also reported to have a mild phenotype (Drendel et al., 2015). We interpret the T351I variant as likely pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000199 SCV001156700 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-03-19 criteria provided, single submitter clinical testing The ACADM c.1052C>T; p.Thr351Ile variant (rs766140986), also known as p.Thr326Ile in traditional nomenclature, is reported in the literature in a mother and son mildly affected with MCAD deficiency, both of whom carried the variant in trans to the common pathogenic p.Lys329Glu variant (Drendel 2015). This variant is found on a single chromosome (1/251370 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported in ClinVar (Variation ID: 203542). The threonine at codon 351 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Although this variant is reported in association with a mild disease presentation (Drendel 2015), based on available information, it is considered to be likely pathogenic. References: Drendel HM et al. Intermediate MCAD Deficiency Associated with a Novel Mutation of the ACADM Gene: c.1052C>T. Case Rep Genet. 2015;2015:532090.
Invitae RCV001000199 SCV001589162 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 351 of the ACADM protein (p.Thr351Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs766140986, ExAC 0.001%). This variant has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 26798524, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 203542). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5
Natera, Inc. RCV001000199 SCV001461475 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-09-16 no assertion criteria provided clinical testing

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