ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.469-9A>G (rs181322317)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211511 SCV000268505 benign Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000251406 SCV000301505 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV001706209 SCV000526101 likely benign not provided 2019-04-09 criteria provided, single submitter clinical testing
Invitae RCV000211511 SCV000630288 benign Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000251406 SCV000918380 likely benign not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: ACADM c.469-9A>G alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00074 in 262480 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0074 in the gnomAD database. The observed variant frequency within African control individuals is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in ACADM causing Medium Chain Acyl-CoA Dehydrogenase Deficiency phenotype (0.0054), suggesting that the variant is a benign polymorphism found primarily in populations of African origin. To our knowledge, no occurrence of c.469-9A>G in individuals affected with Medium Chain Acyl-CoA Dehydrogenase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000211511 SCV001253679 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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