Submissions for variant NM_020297.4(ABCC9):c.2238-1G>A

gnomAD frequency: 0.00056  dbSNP: rs141281214

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172511	SCV000051512	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000150119	SCV000196949	uncertain significance	not specified	2015-03-06	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The c.2238-1G>A var iant in ABCC9 has been identified by our laboratory in two individuals with DCM, one of whom carried a second pathogenic variant in another gene. It has also be en identified in 0.7% (118/16384) of South Asian chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs141281214). This frequency raises doubt as to whether this variant can cause a dominant disease. However, this variant is expected to abolish the 3? splice site of exon 18 and create a novel spice site 3 bases further downstream, which would result in an i n-frame deletion of one amino acid. In summary, additional information is needed to fully assess the clinical significance of the c.2238-1G>A variant.
GeneDx	RCV000172511	SCV000235659	benign	not provided	2018-11-27	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26656175, 28166811, 23861362, 29030401, 28881617, 26046366, 30847666)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001081898	SCV000639226	benign	Dilated cardiomyopathy 1O	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622123	SCV000736304	benign	Cardiovascular phenotype	2018-12-03	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.
Illumina Laboratory Services, Illumina	RCV004528872	SCV001269591	uncertain significance	ABCC9-related disorder	2017-10-18	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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	RCV001170963	SCV001333622	benign	Cardiomyopathy	2018-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000150119	SCV001339240	uncertain significance	not specified	2020-03-16	criteria provided, single submitter	clinical testing	Variant summary: ABCC9 c.2238-1G>A is located in a canonical splice-site, which are typically predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. In the case of this variant, however, 4/4 computational tools predict that the variant abolishes a 3' acceptor site, but strengthens or creates a cryptic 3' acceptor site three bases downstream, which would be predicted to result in the deletion of only one amino acid from the protein. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0015 in 243104 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 59- fold the estimated maximal expected allele frequency for a pathogenic variant in ABCC9 causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. c.2238-1G>A has been reported in the literature in individuals affected with Cardiomyopathy (examples- Bottillo_2016, Cirino_2017, Seidelmann_2017). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They cited the variant as benign (n=1), likley benign (n=2), and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV000172511	SCV004010140	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	ABCC9: BS2
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989328	SCV004807459	likely benign	Hypertrichotic osteochondrodysplasia Cantu type	2024-03-26	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000172511	SCV001743340	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000172511	SCV001797946	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000150119	SCV001925988	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528872	SCV004772993	likely benign	ABCC9-related disorder	2023-10-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).