ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.1063G>T (p.Ala355Ser) (rs145455570)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767008 SCV000620068 uncertain significance not provided 2017-08-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ABCC9 gene. The A355S variant has not been published as pathogenic or been reported as benign to our knowledge. The A355S variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A355S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, though serine (S) is the wild-type amino acid at this position in at least two species. In addition, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000038579 SCV000062257 uncertain significance not specified 2011-11-14 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The Ala355Ser v ariant is listed in dbSNP without frequency information (rs 145455570). This var iant was identified in 1 individual with DCM out of >350 Caucasian individuals t ested by our laboratory. This individual carried a second, likely pathogenic var iant in the TPM1 gene that had occurred do novo, providing strong support for pa thogenicity. Alanine (Ala) at position 355 is conserved in evolution, suggestin g that a change would not be tolerated. In addition, three computer tools (Align GVGD, Polyphen2, SIFT) predict this change to be deleterious; however, their acc uracy is unknown. The available information for this variant is so far consisten t with a pathogenic role but is insufficient to determine its clinical significa nce with certainty, particularly in light of its presence in the proband?s repor tedly unaffected mother.

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