ClinVar Miner

Submissions for variant NM_020297.4(ABCC9):c.4512+814C>T

dbSNP: rs387906805
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000769372 SCV000900760 uncertain significance Cardiomyopathy 2017-06-26 criteria provided, single submitter clinical testing
Loeys Lab, Universiteit Antwerpen RCV001375633 SCV001572558 uncertain significance Hypertrophic cardiomyopathy 2021-02-26 criteria provided, single submitter clinical testing This sequence change results in a missense variant in the ABCC9 gene (p.(Thr1547Ile)). This variant is not present in population databases (absent from GnomAD; PM2). This variant has been reported in the literature in individuals with atrial fibrillation(Olsen et. al; 2007). Functional data are available: Patch-clamp analysis demonstrated that the variant compromised ATP-dependent induction of K-current. Kir6.2-Knock-out mice developed AF in response to adrenergic stimulus. (Olsen et. al; 2007; PS3). Prediction programs showed conflicting results (Align GVGD: G0; PolyPhen-2HumDiv and HumVar: benign; SIFT: tolerated; Mutation taster: disease causing). The variant affects a highly conserved nucleotide and weakly conserved amino acid. The variant was identified in a family with HCM, however it did not show segregation with the HCM-phenotype (BS4). In conclusion this variant was classified as a variant of unknown significance according to ACMG-guidelines (Conflicting results: PM2,PS3, BS4).
Labcorp Genetics (formerly Invitae), Labcorp RCV001852012 SCV002179722 uncertain significance Dilated cardiomyopathy 1O 2022-10-17 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1547 of the ABCC9 protein (p.Thr1547Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ABCC9-related conditions (PMID: 17245405). ClinVar contains an entry for this variant (Variation ID: 30185). 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. Experimental studies have shown that this missense change affects ABCC9 function (PMID: 17245405). 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.
OMIM RCV000023103 SCV000044394 pathogenic Atrial fibrillation, familial, 12 2007-02-01 no assertion criteria provided literature only

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