Submissions for variant NM_001267550.2(TTN):c.54812-5A>G

gnomAD frequency: 0.00078  dbSNP: rs375343798

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152306	SCV000201176	likely benign	not specified	2015-04-28	criteria provided, single submitter	clinical testing	c.47108-5A>G in intron 231 of TTN: This variant is not expected to have clinical significance because it has been identified in 0.45% (11/2470) African chromoso mes by the Exome Aggregation Consortium (http://exac.broadinstitute.org; dbSNP r s375343798).
GeneDx	RCV000152306	SCV000236659	benign	not specified	2014-09-15	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.
Invitae	RCV001082262	SCV000555454	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000152306	SCV000700709	likely benign	not specified	2017-01-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000714054	SCV000844719	benign	not provided	2018-03-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000714054	SCV001472190	likely benign	not provided	2019-11-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840088	SCV002100504	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840089	SCV002100505	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840090	SCV002100506	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001840087	SCV002100507	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000152306	SCV002555939	benign	not specified	2022-06-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.47108-5A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.00024 in 98144 control chromosomes, predominantly at a frequency of 0.0033 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 8 fold of the estimated maximal expected allele frequency for a pathogenic variant in TTN causing Dilated Cardiomyopathy phenotype (0.00039), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.47108-5A>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002433664	SCV002752029	benign	Cardiovascular phenotype	2019-05-15	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486677	SCV004239950	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000152306	SCV001924688	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000714054	SCV001962861	likely benign	not provided		no assertion criteria provided	clinical testing