ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.683C>A (p.Thr228Asn) (rs149678400)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000185662 SCV000238580 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing Both the T228N variant and the G221R variant have been reported in compound heterozygous individuals with biochemical findings consistent with medium chain acyl-CoA dehydrogenase (MCAD) deficiency, although it was not determined if the variants were in cis or trans (McKinney et al., 2004; Smith et al., 2010). The T228N variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Threonine are tolerated across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in a nearby residue (I233T) has been reported in the Human Gene Mutation Database in association with MCAD deficiency (Stenson et al., 2014), supporting the functional importance of this region of the protein. Therefore, based on the currently available information, it is unclear whether the T228N variant is a pathogenic variant or a rare benign variant.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211555 SCV000268480 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Invitae RCV000211555 SCV000754910 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 228 of the ACADM protein (p.Thr228Asn). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs149678400, ExAC 0.2%). This variant has been reported in combination with another ACADM variant in individuals affected with known or suspected MCAD deficiency (PMID: 15171998 20434380, 23842438, Invitae). ClinVar contains an entry for this variant (Variation ID: 203538). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic RCV000185662 SCV001715539 uncertain significance not provided 2020-02-17 criteria provided, single submitter clinical testing

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