Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
ARUP Laboratories, |
RCV001002300 | SCV001160186 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2018-12-26 | criteria provided, single submitter | clinical testing | The ACADM c.216+2T>C variant (rs398123073) has been described in the compound heterozygous state in at least one individual with medium chain acyl-CoA dehydrogenase (MCAD) deficiency (Purevsuren 2012). It is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant abolishes the canonical splice donor site of intron 3, which is likely to disrupt gene function. Additionally, another variant that affects this native splice donor site (c.216+1G>T) has been reported in an individual with MCAD deficiency (Touw 2012). Based on available information, the c.216+2T>C variant is considered pathogenic. REFERENCES Purevsuren J et al. Clinical and molecular aspects of Japanese children with medium chain acyl-CoA dehydrogenase deficiency. Mol Genet Metab. 2012 Sep;107(1-2):237-40. Touw C et al. Risk stratification by residual enzyme activity after newborn screening for medium-chain acyl-CoA dehyrogenase deficiency: data from a cohort study. Orphanet J Rare Dis. 2012 May 25;7:30. |
Invitae | RCV001002300 | SCV003523310 | pathogenic | Medium-chain acyl-coenzyme A dehydrogenase deficiency | 2023-01-07 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 811864). This variant is also known as IVS3+2T>C. Disruption of this splice site has been observed in individual(s) with medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency (PMID: 22796001). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects a donor splice site in intron 3 of the ACADM gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ACADM are known to be pathogenic (PMID: 16121256, 20434380). |