ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.3669G>A (p.Thr1223=) (rs146942382)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767167 SCV000589723 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ABCC9 gene. The c.3669 G>A variant has not been published as pathogenic or been reported as benign to our knowledge. The c.3669 G>A variant is observed in 7/66738 (0.01%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Although c.3669 G>A (T1223T) does not alter the predicted amino acid sequence, this substitution occurs at a nucleotide that is conserved across species and is located within the last nucleotide of exon 29. In silico splice prediction programs predict this variant may reduce the efficiency of the natural splice donor site in intron 29, which may lead to aberrant gene splicing. However, in the absence of functional mRNA studies, the physiological consequence of this variant cannot be precisely determined. Furthermore, no splice site variants definitely associated with cardiomyopathy in the ABCC9 gene have been reported in the Human Gene Mutation Database (Stenson et al., 2014). Finally, this variant is also classified as a variant of uncertain significance in ClinVar by two other clinical laboratories (ClinVar SCV000204353.3; SCV000288988.1; Landrum et al., 2016).
Invitae RCV000233741 SCV000288988 uncertain significance Dilated cardiomyopathy 1O 2018-11-20 criteria provided, single submitter clinical testing This sequence change affects codon 1223 of the ABCC9 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ABCC9 protein. It also falls at the last nucleotide of exon 29 of the ABCC9 coding sequence. This variant is present in population databases (rs146942382, ExAC 0.01%) but has not been reported in the literature in individuals with a ABCC9-related disease. ClinVar contains an entry for this variant (Variation ID: 177999). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is present in population databases and is predicted to disrupt mRNA splicing. In the absence of segregation or functional studies, at this time this change has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154675 SCV000204353 uncertain significance not specified 2014-08-21 criteria provided, single submitter clinical testing The Thr1223Thr variant in ABCC9 has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/8600 European American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; d bSNP rs146942382). Although this variant does not alter an amino acid residue, i t is located in the 5' splice region. Computational tools suggest this variant m ay have an impact to splicing; however, this information is not predictive enoug h to determine pathogenicity. In summary, the clinical significance of the Thr12 23Thr variant is uncertain.

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