Submissions for variant NM_001267550.2(TTN):c.25351+13C>G

gnomAD frequency: 0.00090  dbSNP: rs138362885

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040027	SCV000063718	likely benign	not specified	2012-03-19	criteria provided, single submitter	clinical testing	21619+13C>G in intron 84 of TTN: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence. It h as been identified in 0.3% (8/3124) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs138362885). 21619+13C>G in intron 84 of TTN (rs138362885; allele f requency = 0.3%, 8/3124) **
GeneDx	RCV000040027	SCV000515104	likely benign	not specified	2017-11-30	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000040027	SCV002041822	benign	not specified	2021-11-29	criteria provided, single submitter	clinical testing	Variant summary: TTN c.21619+13C>G alters a non-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 0.00027 in 260612 control chromosomes, predominantly at a frequency of 0.0028 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7-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.21619+13C>G in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV001839560	SCV002102027	benign	Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839561	SCV002102028	benign	Myopathy, myofibrillar, 9, with early respiratory failure	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839562	SCV002102029	benign	Early-onset myopathy with fatal cardiomyopathy	2021-09-10	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001839559	SCV002102032	benign	Tibial muscular dystrophy	2021-09-10	criteria provided, single submitter	clinical testing
Invitae	RCV002054777	SCV002477504	benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-20	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000040027	SCV001918291	benign	not specified		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001725952	SCV001962942	likely benign	not provided		no assertion criteria provided	clinical testing