Submissions for variant NM_020297.4(ABCC9):c.1987C>T (p.Arg663Cys)

gnomAD frequency: 0.00014  dbSNP: rs200349671

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2021-08-12	criteria provided, single submitter	clinical testing	Reported in one individual with early repolarization syndrome, a history of ventricular tachycardia/fibrillation, and syncope (Hu et al., 2014), in one patient referred for DCM genetic testing (Walsh et al., 2017) and in one patient with arrhythmia that presented after a high voltage electrical shock (Treat et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID#45395; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 34281161, 24439875, 27532257)
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	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 663 of the ABCC9 protein (p.Arg663Cys). This variant is present in population databases (rs200349671, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of early repolarization syndrome or dilated cardiomyopathy (PMID: 24439875, 27532257). ClinVar contains an entry for this variant (Variation ID: 45395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ABCC9 protein function with a negative predictive value of 95%. 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
Fulgent Genetics, Fulgent Genetics	RCV002490525	SCV002794096	uncertain significance	Hypertrichotic osteochondrodysplasia Cantu type; Dilated cardiomyopathy 1O; Atrial fibrillation, familial, 12; Intellectual disability and myopathy syndrome	2021-10-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004018877	SCV005023079	likely benign	Cardiovascular phenotype	2023-11-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.