ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.1247T>C (p.Ile416Thr) (rs760892123)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185669 SCV000238588 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing The I416T missense change in the ACADM gene has not been reported as a benign polymorphism. It has been reported previously in three patients detected by positive newborn screening results for medium chain acyl-CoA dehydrogenase (MCAD) deficiency who also harbored the K329E mutation (Smith et al., 2010 Couce et al., 2011). Biochemical analyses on these patients and in-silico analysis of I416T led the authors to conclude that this missense change was a variant of unknown significance. I416T is a non-conservative amino acid change in that a non-polar Isoleucine residue is replaced by a polar Threonine residue. This change occurs at a position that is highly conserved in the ACADM protein in mammals; however, this position is not highly conserved outside mammals or in related proteins. Multiple in-silico analysis models predict that I416T is a benign sequence change. Therefore, based on the currently available information, it is unclear whether I416T is a disease-causing mutation or a rare benign variant. The variant is found in ACADM panel(s).
Invitae RCV000556896 SCV000630278 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 416 of the ACADM protein (p.Ile416Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs760892123, ExAC 0.01%). This variant has been reported in individuals affected with MCAD deficiency co-occurring with the pathogenic ACADM variant p.Lys329Glu but the phase was not resolved (PMID: 20434380, 23430840, Invitae). In addition, it has been reported to co-occur with a rare ACADM missense variant in an individual with mildly elevated levels of C8 (PMID: 26947917). ClinVar contains an entry for this variant (Variation ID: 203543). Experimental studies have shown that this missense has a mild effect on protein function (PMID: 26947917). In summary, this variant is a rare missense change that has been found in affected individuals co-occurring with pathogenic variants in the ACADM gene. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000556896 SCV000798902 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-03-28 criteria provided, single submitter clinical testing

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