ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.616C>T (p.Arg206Cys) (rs373715782)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077892 SCV000232455 pathogenic not provided 2012-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000077892 SCV000238579 pathogenic not provided 2015-12-11 criteria provided, single submitter clinical testing The R206C mutation has been reported previously in individuals with a positive newborn screen result for medium chain acyl-CoA dehydrogenase (MCAD) deficiency as has another missense mutation at the same position. In vitro experiments show that R206C is a folding variant (Maier et al., 2009). A patient who is homozygous for R206C showed very mild biochemical markers of MCAD (Maier et al., 2005). However, patients with mild biochemical markers in newborn screening may still develop clinical symptoms of MCAD deficiency (Maier et al., 2009). Therefore, we interpret that individuals harboring the R206C mutation should still be considered at risk for developing clinical manifestations. The variant is found in ACADM panel(s).
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000505848 SCV000268479 likely pathogenic not specified 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000180087 SCV000630292 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 206 of the ACADM protein (p.Arg206Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported as homozygous or in combination with another ACADM variant in individuals affected with medium-chain acyl-CoA dehydrogenase deficiency (PMID:15832312, 23028790, 20434380, 16291504). This variant is also known as Arg181Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 92267). Experimental studies have shown that this missense change affects folding of the ACADM protein, decreases the thermal stability of the protein and increases its susceptibility to proteolysis, and reduces affinity for the enzyme's substrate (PMID: 24718418, 19224950). A different missense substitution at this codon (p.Arg206Leu) has been determined to be likely pathogenic (PMID: 10767181). This suggests that the arginine residue is critical for ACADM protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077892 SCV000887495 pathogenic not provided 2018-06-07 criteria provided, single submitter clinical testing
Counsyl RCV000180087 SCV000485316 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-11-17 no assertion criteria provided clinical testing
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City RCV000180087 SCV001469160 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-11-12 no assertion criteria provided clinical testing

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