ClinVar Miner

Submissions for variant NM_005691.3(ABCC9):c.3594G>A (p.Met1198Ile) (rs199900459)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000171850 SCV000050871 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769375 SCV000900765 uncertain significance Cardiomyopathy 2016-07-13 criteria provided, single submitter clinical testing
GeneDx RCV000171850 SCV000536154 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ABCC9 gene. The M1198I variant was reported as a variant of uncertain significance in one individual from a cohort that was not selected for cardiomyopathy, arrhythmia, or family history of sudden cardiac death, who underwent exome sequencing (Ng et al., 2013). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; Exome Variant Server). The M1198I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis suggests that this variant is probably damaging to the protein structure/function. However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000465122 SCV000551687 uncertain significance Dilated cardiomyopathy 1O 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 1198 of the ABCC9 protein (p.Met1198Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs199900459, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with left ventricular non-compaction and Rubinstein-Taybi syndrome, who also has a nonsense variant in CREBBP (PMID: 25979592). ClinVar contains an entry for this variant (Variation ID: 191584). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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