ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.928G>A (p.Gly310Arg) (rs747268471)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000724339 SCV000224737 uncertain significance not provided 2014-10-31 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000173613 SCV000268501 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
Invitae RCV000173613 SCV000754918 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 310 of the ACADM protein (p.Gly310Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs747268471, ExAC 0.01%). This variant has been reported in combination with other pathogenic or likely pathogenic ACADM variants in individuals affected with MCAD deficiency (PMID: 23509891, 18241067, 20434380), and in an asymptomatic individual newborn screening positive for acylcarnitine profile (PMID: 11349232). ClinVar contains an entry for this variant (Variation ID: 193539). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000173613 SCV000918376 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-11-20 criteria provided, single submitter clinical testing Variant summary: The ACADM c.928G>A (p.Gly310Arg) variant involves the alteration of a highly conserved nucleotide. The variant is located within the conserved Acyl-CoA dehydrogenase/oxidase C-terminal domain (InterPro) and 5/5 in silico tools predict a damaging outcome for this variant. These predictions were confirmed by functional studies, where G310R was shown to be defective and unstable due to compromised folding (Andresen_ 2001). This variant was found in 6/275998 control chromosomes in gnomAD at a frequency of 0.000021, which does not exceed the estimated maximal expected allele frequency of a pathogenic ACADM variant (0.0054006). The variant was identified in several affected individuals with biochemical profiles suggestive of an intermediate MCAD phenotype (Andresen_ 2001, Smith_2010, Touw_2013, Nichols_2008). The variant has been reported with conflicting interpretations of pathogenicity (VUS/Pathogenic) by different clinical diagnostic laboratories/reputable databases. Taken together, this variant is classified as Likely Pathogenic.

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