ClinVar Miner

Submissions for variant NM_020297.3(ABCC9):c.1987C>T (p.Arg663Cys) (rs200349671)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000038592 SCV000062270 uncertain significance not specified 2011-07-28 criteria provided, single submitter clinical testing The Arg663Cys variant has not been reported in the literature, but has been dete cted in 1 individual with DCM out of >300 Caucasian probands tested by our labor atory. Arginine (Arg) at position 663 is highly conserved across several evolut ionarily distant species, suggesting that a change would not be tolerated. In ad dition, three computer tools (AlignGVGD, Polyphen2, SIFT) predict this change to be deleterious; however, their accuracy is unknown. In summary, the available information for this variant is so far consistent with a pathogenic role but add itional studies (such as control and segregation studies) are needed to determin e its clinical significance with certainty.
GeneDx RCV000767084 SCV000516093 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing The R663C variant of uncertain significance in the ABCC9 gene has been reported in one individual with early repolarization syndrome, a history of ventricular tachycardia/fibrillation and syncope (Hu et al., 2014) and in one patient referred for DCM genetic testing (Walsh et al., 2017); however, segregation information and functional studies were not provided. The R663C variant is observed 29/277092 (0.01%) alleles from individuals of multiple ethnic backgrounds in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Nonetheless, the R663C 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. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Mendelics RCV000988800 SCV001138663 uncertain significance Dilated cardiomyopathy 1O 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000988800 SCV001420780 uncertain significance Dilated cardiomyopathy 1O 2019-11-18 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 663 of the ABCC9 protein (p.Arg663Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs200349671, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with clinical features of early repolarization syndrome or dilated cardiomyopathy (PMID: 27532257, 24439875). ClinVar contains an entry for this variant (Variation ID: 45395). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256792 SCV001433241 uncertain significance Dilated cardiomyopathy 1A 2019-11-08 criteria provided, single submitter clinical testing

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