Submissions for variant NM_020297.4(ABCC9):c.2200G>A (p.Val734Ile)

gnomAD frequency: 0.00769  dbSNP: rs61688134

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172738	SCV000051513	benign	Myocardial infarction	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038600	SCV000062278	benign	not specified	2012-02-17	criteria provided, single submitter	clinical testing	Val734Ile in exon 17 of ABCC9: This variant is not expected to be clinically sig nificant because it has been identified in 1.2% (87/7012) of European American c hromosomes chromosomes from a broad population by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS; dbSNP rs61688134). Minoretti and colleag ues (2006) reported a possible association with an increased risk for myocardial infarction (based on an increased frequency in cases compared to controls), tho ugh this variant is unlikely to be disease causing when present in isolation.
GeneDx	RCV000038600	SCV000166793	benign	not specified	2014-03-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082826	SCV000262065	benign	Dilated cardiomyopathy 1O	2024-01-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000038600	SCV000313468	benign	not specified		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000251925	SCV000317866	benign	Cardiovascular phenotype	2015-09-24	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000038600	SCV000698648	benign	not specified	2021-03-30	criteria provided, single submitter	clinical testing	Variant summary: ABCC9 c.2200G>A (p.Val734Ile) results in a conservative amino acid change located in the ABC transporter-like (IPR003439) and AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This variant is also located in an exonic splice region altering the second nucleotide of exon 17. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0073 in 253636 control chromosomes, predominantly at a frequency of 0.012 within the Non-Finnish European subpopulation in the gnomAD database, including 7 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 480 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2200G>A has been reported in the literature in individuals affected with cardiomyopathy, myocardial infarction, arrhythmia (example, Zimmerman 2010, Bottillo 2016, Minoretti 2006, Hu 2013, Celestino-Soper 2015). These report(s) do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. Co-occurrences with other pathogenic variant(s) have been observed in patients undergoing panel testing for HCM (hypertrophic cardiomyopathy) at our laboratory and in the literature (example, MYBPC3 c.1484G>A, p.Arg495Gln, our laboratory; MYBPC3 c.2309-2A>G, Bottillo_2016) and SCN5A 3891insA in a proband with sinus bradycardia, AV block, ventricular bigeminy and a global ER pattern (Hu_2013), providing supporting evidence for a benign role. At least two publications reporting experimental evidence evaluating an impact on protein function were ascertained in the context of this evaluation. These reported that the variant, p.Val734Ile, may affect the function of ABCC9 potassium ATP channel complex. However the in-vivo physiological consequences of these findings are not cleary established (Smith_2013, Hu_2013). In a case-control study that included 584 Precocious Myocardial Infarction (PMI) patients and 873 controls, the frequency of 734Ile carriers was significantly higher in MI patients as compared to controls (crude OR=5.52, 95% CI=1.53-19.84, P=0.0075) (Minoretti 2006). However, larger cohort studies are needed to confirm whether this variant is associated with Precocious Myocardial Infarction. Therefore, these studies does not allow convincing conclusions about the variant effect. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign, n=4; likely benign, n=1; VUS, n=1). Based on the evidence outlined above and the predominant consensus among peers supporting a non-actionable outcome in an inherited germline setting, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001528354	SCV000884940	benign	not provided	2023-11-03	criteria provided, single submitter	clinical testing
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852670	SCV000995377	benign	Cardiomyopathy; Ventricular tachycardia	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001082826	SCV001269592	uncertain significance	Dilated cardiomyopathy 1O	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000029274	SCV001333623	likely benign	Cardiomyopathy	2017-11-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001528354	SCV003917185	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ABCC9: BS1, BS2
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528354	SCV001739979	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000038600	SCV001922749	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000038600	SCV001927480	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000038600	SCV001956145	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000038600	SCV001973773	benign	not specified		no assertion criteria provided	clinical testing