Submissions for variant NM_001267550.2(TTN):c.18172C>T (p.Arg6058Cys)

gnomAD frequency: 0.00053  dbSNP: rs189127014

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000726954	SCV000238249	likely benign	not provided	2021-03-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000543023	SCV000642751	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2017-12-28	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000726954	SCV000704421	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185356	SCV000710966	uncertain significance	not specified	2016-05-27	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The p.Arg4814Cys va riant in TTN has not been previously reported in individuals with cardiomyopathy , but has been identified in 0.1% (10/9720) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs189127014) . Arginine (Arg) at position 4814 is not conserved in evolutionarily distant spe cies and 10 species of fish carry the variant cysteine (Cys), supporting that th is change may be tolerated. In summary, while the clinical significance of the p .Arg4814Cys variant is uncertain, these data suggest that it is more likely to b e benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185356	SCV001519427	likely benign	not specified	2021-03-15	criteria provided, single submitter	clinical testing	Variant summary: TTN c.14440C>T (p.Arg4814Cys) results in a non-conservative amino acid change located in the I-band domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 279664 control chromosomes, predominantly at a frequency of 0.0015 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 4 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.14440C>T in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
New York Genome Center	RCV002274948	SCV002564369	uncertain significance	Dilated cardiomyopathy 1G; Hypertrophic cardiomyopathy 9	2021-08-20	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000726954	SCV003820184	uncertain significance	not provided	2021-11-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486763	SCV004239839	benign	Cardiomyopathy	2022-11-09	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000726954	SCV001924331	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000726954	SCV001967580	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000726954	SCV002034971	uncertain significance	not provided		no assertion criteria provided	clinical testing