ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.799G>A (p.Gly267Arg) (rs121434274)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000003771 SCV000268497 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000185665 SCV000281623 pathogenic not provided 2016-02-23 criteria provided, single submitter clinical testing
Counsyl RCV000003771 SCV000677966 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-09-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000185665 SCV000232890 pathogenic not provided 2014-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000185665 SCV000238583 pathogenic not provided 2016-09-09 criteria provided, single submitter clinical testing The G267R missense variant in the ACADM gene has been reported previously in association with medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (Yokota et al. 1991; Koster et al. 2014; Sturm et al. 2012). Expression studies found that G267R is associated with reduced (13% to less than 10%) residual MCAD enzyme activity compared to wild-type and low/no protein expression on Western blot analysis (Koster et al. 2014; Sturm et al. 2012). Therefore, we interpret G267R to be a pathogenic variant.
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000003771 SCV000845512 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-08-07 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000003771 SCV000915432 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-08-14 criteria provided, single submitter clinical testing The ACADM c.799G>A (p.Gly267Arg) missense variant has been reported in several studies in association with MCAD deficiency. Across a selection of available literature, the p.Gly267Arg variant has been found in at least 12 individuals affected with MCAD deficiency, in at least six in a compound heterozygous state, and in at least six in a homozygous state (Yokota et al. 1991; Zschocke et al. 2001; Maier et al. 2005; Sturm et al. 2012; Anderson et al. 2012). In general, the individuals who were homozygous for the variant were asymptomatic or presented with a mild phenotype, while individuals who were compound heterozygous for the variant displayed a moderate to severe phenotype (Maier et al. 2005; Sturm et al. 2012; Anderson et al. 2012). The p.Gly267Arg variant was found in two unaffected parents in a heterozygous state (Zschocke et al. 2001) and was absent from at least 12 controls. The p.Gly267Arg variant is reported at a frequency of 0.000487 in the South Asian population of the Genome Aggregation Database. The Gly267 residue is conserved. Expression studies of the p.Gly267Arg variant in E. coli revealed considerable residual MCAD activity of the protein (40%) compared to wild type (Andresen et al. 1997). In vitro activity of the p.Gly267Arg protein was markedly increased when co-expressed with GroESL chaperonins, indicating that the variant affects protein folding (Andresen et al. 1997). Another set of studies in E. coli showed that the p.Gly267Arg variant had low activity of <5% and was expressed at very low levels. This residue is predicted to be localized in a domain of beta-sheets involved in Flavin adenine nucleotide (FAD) binding (Koster et al. 2014). Based on the collective evidence, the p.Gly267Arg variant is classified as pathogenic for MCAD deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America RCV000003771 SCV000693959 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2016-09-22 criteria provided, single submitter clinical testing Variant summary: The ACADM c.799G>A (p.Gly267Arg) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant, which was confirmed by at least one functional study (Sturm_2012). This variant was found in 26/121212 control chromosomes at a frequency of 0.0002145, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant (0.0054233). The variant has been reported in numerous affected individuals in the literature in both the homozygous and compound heterozygous state (Andresen_2012, Sturm_2012, Gramer_2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000003771 SCV000630297 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 267 of the ACADM protein (p.Gly267Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121434274, ExAC 0.04%). This variant has been reported in the literature in several individuals affected with MCAD deficiency as homozygous or in combination with other ACADM variants (PMID: 23028790, 16291504, 1684086, 22848008, Invitae). ClinVar contains an entry for this variant (Variation ID: 3588). Experimental studies have shown that this missense change causes folding defects and a reduced enzymatic activity in the ACADM protein (PMID: 9158144, 24966162). In summary, this variant is a rare missense change that has been reported in several affected individuals and has shown a deleterious effect in protein function. For these reasons, it has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000003771 SCV000967652 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-10-24 criteria provided, single submitter clinical testing The p.Gly271Arg (NM_001127328.1 c.811G>A) variant in ACADM (also reported as NM_ 000016.4:p.Gly267Arg in the literature) has been reported in at least 4 homozygo us and 5 compound heterozygous individuals with medium-chain acyl-coenzyme A deh ydrogenase (MCAD) deficiency (Yokota 1991, Zschocke 2001, Sturm 2012, and Koster 2014). This variant has also been reported in ClinVar (Variation ID#3588) as pa thogenic by multiple laboratories. It has been identified in 34/126698 of Europe an chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadin stitute.org; dbSNP rs121434274), though this frequency is low enough to be consi stent with a recessive carrier frequency. In vitro functional studies suggest t hat the p.Gly271Arg variant leads to reduced activity (Zschocke 2001, Sturm 2012 , and Koster 2014). In summary, the p.Gly271Arg variant is pathogenic for MCAD d eficiency in an autosomal recessive manner based upon observations in affected i ndividuals and functional studies. ACMG/AMP Criteria applied: PS3, PM3 (upgraded to strong based on multiple occurrences),PP3;PP5 (Richards 2015).
OMIM RCV000003771 SCV000023936 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 1991-12-01 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000185665 SCV000887497 pathogenic not provided 2018-08-24 criteria provided, single submitter clinical testing

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