ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.580A>G (p.Asn194Asp) (rs773677327)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211463 SCV000268495 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Invitae RCV000211463 SCV000630290 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-05 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 194 of the ACADM protein (p.Asn194Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs773677327, ExAC 0.02%). This variant has been reported as homozygous and in combination with another ACADM variant in individuals affected with MCAD deficiency (PMID: 18241067, 20434380, 23700290, 27751224). This variant is also known as p.N169D in the literature. ClinVar contains an entry for this variant (Variation ID: 226100). 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: Tolerated; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755768 SCV000883326 likely pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing The ACADM c.580A>G; p.Asn194Asp variant (rs773677327), also published as Asn169Asp, is reported in the medical literature in individuals with MCAD deficiency in both the homozygous state and in individuals with an additional pathogenic variant (Chien 2013, Nichols 2008, Smith 2010). The variant is listed in the ClinVar database (Variation ID: 226100) and in the Genome Aggregation Database in 5 out of 246188 alleles, indicating it is not a common polymorphism. The asparagine at codon 194 is highly conserved and computational analysis (PolyPhen-2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Chien YH et al. Fatty Acid oxidation disorders in a chinese population in taiwan. JIMD Rep. 2013;11:165-72. Nichols MJ et al. Novel mutations causing medium chain acyl-CoA dehydrogenase deficiency: under-representation of the common c.985 A > G mutation in the New York state population. Am J Med Genet A. 2008 Mar 1;146A(5):610-9. Smith EH et al. Allelic diversity in MCAD deficiency: the biochemical classification of 54 variants identified during 5 years of ACADM sequencing. Mol Genet Metab. 2010 Jul;100(3):241-50.
GeneDx RCV000755768 SCV001801750 uncertain significance not provided 2020-09-15 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23700290, 20434380, 18241067, 27751224)
Counsyl RCV000211463 SCV001132318 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-02-15 no assertion criteria provided clinical testing

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