Submissions for variant NM_000016.6(ACADM):c.580A>G (p.Asn194Asp)

gnomAD frequency: 0.00002  dbSNP: rs773677327

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000211463	SCV000630290	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 194 of the ACADM protein (p.Asn194Asp). This variant is present in population databases (rs773677327, gnomAD 0.01%). This missense change has been observed in individual(s) with MCAD deficiency (PMID: 18241067, 20434380, 23700290, 27751224). This variant is also known as p.N169D. ClinVar contains an entry for this variant (Variation ID: 226100). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACADM protein function. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000211463	SCV000883326	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	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	likely pathogenic	not provided	2023-09-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); 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: 27751224, 18241067, 20434380, 34394177, 30675864, 32778825, 37308883, 23700290)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211463	SCV003845148	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-02-24	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.580A>G (p.Asn194Asp) results in a conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251392 control chromosomes (gnomAD). c.580A>G has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (example: Nichols_2008, Chien_2013, Tan_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant (condition: Medium-chain acyl-coenzyme A dehydrogenase deficiency) to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV000211463	SCV004212180	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-02-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000211463	SCV001132318	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2019-02-15	no assertion criteria provided	clinical testing