Submissions for variant NM_001267550.2(TTN):c.20630T>C (p.Ile6877Thr)

gnomAD frequency: 0.00103  dbSNP: rs142794598

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000172693	SCV000055056	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154985	SCV000204667	likely benign	not specified	2015-04-24	criteria provided, single submitter	clinical testing	p.Ile5633Thr in exon 68 of TTN: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (37/9774) of African chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; db SNP rs142794598).
Eurofins Ntd Llc (ga)	RCV000154985	SCV000231970	likely benign	not specified	2017-01-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000172693	SCV000238284	likely benign	not provided	2021-06-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23861362)
Invitae	RCV001081624	SCV000555280	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing
Athena Diagnostics Inc	RCV000172693	SCV000616019	likely benign	not provided	2018-03-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000172693	SCV001473651	uncertain significance	not provided	2019-11-11	criteria provided, single submitter	clinical testing	The TTN c.20630T>C; p.Ile6877Thr variant (rs142794598; ClinVar Variation ID: 178246) is rare in the general population (<1% allele frequency in the Genome Aggregation Database) and has not been reported in the medical literature in association with dilated cardiomyopathy (DCM) or other TTN-related disease. The clinical relevance of rare missense variants in this gene, which are identified on average once per individual sequenced in affected populations (Herman 2012), is not well understood. Yet, evidence suggests that the vast majority of such missense variants do not contribute to the clinical outcome of DCM (Begay 2015). Thus, the clinical significance of this variant cannot be determined with certainty.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154985	SCV002555937	likely benign	not specified	2023-06-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.16898T>C (p.Ile5633Thr) results in a non-conservative amino acid change located in the I-band of the encoded protein sequence. One of two in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 247418 control chromosomes, predominantly at a frequency of 0.0038 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 9.73 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.16898T>C in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486695	SCV004239845	benign	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003927499	SCV004740629	likely benign	TTN-related condition	2022-03-18	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).