ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.583G>A (p.Gly195Arg) (rs121434278)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000003777 SCV000268477 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Counsyl RCV000003777 SCV000220190 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2014-03-24 criteria provided, single submitter literature only
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000077891 SCV000231983 pathogenic not provided 2013-11-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000003777 SCV000893474 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000077891 SCV000511932 pathogenic not provided 2017-05-01 criteria provided, single submitter clinical testing The G195R pathogenic variant in the ACADM gene has been reported previously in association with medium chain acyl-CoA dehydrogenase (MCAD) deficiency and, when expressed in bacteria, this variant encodes a medium chain acyl-CoA dehydrogenase protein that is devoid of enzyme activity (Brackett et al., 1994).
Integrated Genetics/Laboratory Corporation of America RCV000003777 SCV000918378 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-05-11 criteria provided, single submitter clinical testing Variant summary: ACADM c.583G>A (p.Gly195Arg) results in a non-conservative amino acid change located in the Acyl-CoA oxidase/dehydrogenase, central domain 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 3.6e-05 in 277130 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency (3.6e-05 vs 0.0054), allowing no conclusion about variant significance. The variant, c.583G>A, has been reported in the literature in multiple individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency (Andresen_1997, Gramer_2015). These data indicate that the variant is very likely to be associated with disease. A functional study, Andresen_1997, showed the variant eliminated enzyme activity. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000003777 SCV000630291 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-10-13 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 195 of the ACADM protein (p.Gly195Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs121434278, ExAC 0.004%). This variant has been reported as homozygous or in combination with another ACADM variant in individuals affected with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 25940036, 16291504, 7603790) and it has been reported to segregate with this disease in several families (PMID: 7929823, 9158144). This variant is also known as p.Gly170Arg in the literature. ClinVar contains an entry for this variant (Variation ID: 3594). Experimental studies have shown that this missense change leads to an impairment of biogenesis of the ACADM protein and a lack of enzyme activity in vitro (PMID: 7929823, 9158144). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000003777 SCV000023942 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 1994-10-01 no assertion criteria provided literature only

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