ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.558T>A (p.Asn186Lys) (rs754359356)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000421950 SCV000231984 uncertain significance not provided 2015-04-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000211498 SCV000268459 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2015-02-20 criteria provided, single submitter clinical testing
GeneDx RCV000421950 SCV000511931 likely pathogenic not provided 2016-02-18 criteria provided, single submitter clinical testing A N186K (c.558 T>A) variant that is likely pathogenic was identified in the ACADM gene. This variant has previously been reported in association with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (Andresen et al., 2012). Clinical studies of individuals identified by newborn screening and in vitro experiments indicate that N186K is a mild variant, associated with a milder biochemical phenotype (Andresen et al., 2012). Additionally, several in-silico splice prediction models predict that the c.558 T>A nucleotide substitution, responsible for N186K, creates a strong cryptic splice donor site, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded.
Counsyl RCV000211498 SCV000800531 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2017-05-12 criteria provided, single submitter clinical testing
Invitae RCV000211498 SCV000940988 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2020-10-31 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 186 of the ACADM protein (p.Asn186Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with or on the opposite chromosome (in trans) from another pathogenic variant in in ACADM in individuals affected with Medium-chain acyl-coenzyme A dehydrogenase deficiency (PMID: 22542437, 20434380). This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. ClinVar contains an entry for this variant (Variation ID: 198379). Experimental studies have shown that this missense change results in similar residual enzyme activity to previously published mild ACADM variants (PMID: 22542437). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.

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