ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.797A>G (p.Asp266Gly) (rs201375579)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211538 SCV000268491 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000185664 SCV000883327 pathogenic not provided 2017-10-17 criteria provided, single submitter clinical testing The ACADM c.797A>G, p.Asp266Gly (rs201375579), also known as D241G, has been reported in an individual with medium chain acyl-CoA dehydrogenase deficiency, in-trans with the common p.Lys329Glu pathogenic variant (Maier 2005). Functional characterization of the variant protein indicates reduced enzymatic activity and protein stability, likely due to the defects in monomer folding and tetramer formation (Jank 2014, Maier 2009). The variant is classified as pathogenic in ClinVar (Variation ID: 203540), and observed in the general population databases at a frequency of 0.08 percent in the Exome Variant Server (1/13006 alleles), and 0.03 percent in the Genome Aggregation Database (73/246234 alleles). Based on the above information, the variant is classified as pathogenic. References: Jank J et al. The domain-specific and temperature-dependent protein misfolding phenotype of variant medium-chain acyl-CoA dehydrogenase. PLoS One. 2014; 9(4):e93852. Maier E et al. Population spectrum of ACADM genotypes correlated to biochemical phenotypes in newborn screening for medium-chain acyl-CoA dehydrogenase deficiency. Hum Mutat. 2005; 25(5):443-52. Maier E et al. Protein misfolding is the molecular mechanism underlying MCADD identified in newborn screening. Hum Mol Genet. 2009; 18(9):1612-23.
Fulgent Genetics RCV000211538 SCV000893476 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000185664 SCV000238582 pathogenic not provided 2018-11-16 criteria provided, single submitter clinical testing The D266G missense mutation has been reported previously in a patient who was detected by newborn screening, with follow-up biochemical studies consistent with MCAD deficiency (Maier et al., 2005). Functional studies under thermal stress found that D266G resulted in protein misfolding similar to the K329E mutation and may therefore be classified as just as severe (Jank et al., 2014). The variant is found in FAO-MET panel(s).
Invitae RCV000211538 SCV000630296 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-06-22 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 266 of the ACADM protein (p.Asp266Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs201375579, ExAC 0.2%). This variant has been reported in newborns showing biochemical abnormalities consistent with medium chain acyl-CoA dehydrogenase (MCAD) deficiency  (PMID: 19224950, 22542437, 19780764, Invitae). However, it is uncertain if this variant can cause clinical symptoms (PMID: 20434380). This sequence change is also known as p.Asp241Gly or D241G in the literature. ClinVar contains an entry for this variant (Variation ID: 203540). Experimental studies have shown that this variant impairs the stability of the encoded enzyme and causes partial reduction of enzyme activity (48% of wild type) (PMID: 19224950, 24718418). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostics Laboratory,M Health: University of Minnesota RCV000211538 SCV000891272 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-12-04 criteria provided, single submitter clinical testing

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