Submissions for variant NM_000016.6(ACADM):c.616C>T (p.Arg206Cys)

gnomAD frequency: 0.00001  dbSNP: rs373715782

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV000180087	SCV000630292	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the ACADM protein (p.Arg206Cys). This variant is present in population databases (rs373715782, gnomAD 0.006%). This missense change has been observed in individuals with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 15832312, 16291504, 20434380, 23028790). This variant is also known as Arg181Cys. ClinVar contains an entry for this variant (Variation ID: 92267). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ACADM function (PMID: 19224950, 24718418). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg206 amino acid residue in ACADM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10767181). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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
Revvity Omics, Revvity	RCV000180087	SCV002019831	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2019-10-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077892	SCV004032959	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ACADM: PM3:Strong, PM1, PM2, PM5, PP4:Moderate, PS3:Supporting
Baylor Genetics	RCV000180087	SCV004212113	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000180087	SCV004803312	pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-01-13	criteria provided, single submitter	clinical testing	Variant summary: ACADM c.616C>T (p.Arg206Cys) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, middle domain (IPR006091) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251400 control chromosomes. c.616C>T has been reported in the literature at a compound heterozygous with different pathogenic variants in ACADM in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency or receiving ACADM newborn screening (examples, Maier_2005, Smith_2010, Sturm_2012, Waddell_2006). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15832312, 20434380, 23028790, 16291504). ClinVar contains an entry for this variant (Variation ID: 92267). Based on the evidence outlined above, the variant was classified as pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000180087	SCV004806785	likely pathogenic	Medium-chain acyl-coenzyme A dehydrogenase deficiency	2024-03-26	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