Submissions for variant NM_001267550.2(TTN):c.44077C>T (p.Arg14693Cys)

gnomAD frequency: 0.00083  dbSNP: rs200445568

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724241	SCV000226858	uncertain significance	not provided	2014-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000724241	SCV000237172	likely benign	not provided	2020-10-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000219227	SCV000272647	uncertain significance	not specified	2015-01-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg12125Cys v ariant in TTN has not been previously reported in individuals with cardiomyopath y, but has been identified in 0.2% (20/9970) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs200445568 ). Computational prediction tools and conservation analysis suggest that this va riant may impact the protein, though this information is not predictive enough t o determine pathogenicity. In summary, while the clinical significance of the p. Arg12125Cys variant is uncertain, its frequency suggests that it is more likely to be benign.
Invitae	RCV001079420	SCV000555130	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000618077	SCV000737338	likely benign	Cardiovascular phenotype	2018-12-05	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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	RCV000769015	SCV000900388	benign	Cardiomyopathy	2020-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000219227	SCV001448485	likely benign	not specified	2020-11-16	criteria provided, single submitter	clinical testing	Variant summary: TTN c.36373C>T (p.Arg12125Cys) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 279870 control chromosomes, predominantly at a frequency of 0.0024 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 6 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. c.36373C>T has been reported in the literature in one individual affected with sudden cardiac death (Campuzano_2018). The report does not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004537383	SCV004752398	likely benign	TTN-related disorder	2022-01-31	criteria provided, single submitter	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).
Clinical Genetics, Academic Medical Center	RCV000724241	SCV001920264	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000724241	SCV001967114	likely benign	not provided		no assertion criteria provided	clinical testing