Submissions for variant NM_001267550.2(TTN):c.11254+2T>C

gnomAD frequency: 0.00147  dbSNP: rs199565715

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000155005	SCV000204687	uncertain significance	not specified	2014-05-28	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The 10741+2T>C vari ant in TTN has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.4% (17/3882) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1995 65715). This variant occurs in the invariant region (+/- 1,2) of the splice cons ensus sequence. Splice and other truncating variants in TTN are strongly associa ted with DCM, particularly if they are located in exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014). Variants in the I-band (where th e 10741+2T>C variant is located) occur at greater frequency in controls than in patients (Pugh 2014). This decreases but does not rule out that this variant ha s a role in disease. In summary, while the clinical significance of the 10741+2T >C variant is uncertain, these data suggest that it is more likely to be benign.
GeneDx	RCV000713962	SCV000237027	likely benign	not provided	2020-07-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 26735901)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516117	SCV000261793	likely benign	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-02-13	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000155005	SCV000704242	likely benign	not specified	2017-01-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000155005	SCV000844614	benign	not specified	2019-11-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000713962	SCV001746691	likely benign	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TTN: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000155005	SCV003923278	benign	not specified	2023-03-08	criteria provided, single submitter	clinical testing	Variant summary: TTN c.10303+2764T>C is located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. In a different transcript this variant has also been reported as a splice site variant (i.e. NM_001267550, c.11254+2T>C), however, the PSI value (proportion spliced-in) for the neighboring exon is very low (see e.g. in McAfee_2021), therefore it's significance is unclear. The variant allele was found at a frequency of 0.0013 in 150958 control chromosomes, predominantly at a frequency of 0.0048 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 12 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. The variant, c.10303+2764T>C, has been reported in the literature in individuals affected with cardiomyopathy, however without evidence for causality (Ware_2016, McAfee_2021). These reports do 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 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified as VUS (n=1), Likely benign (n=3) or Benign (n=1). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV004544430	SCV004767533	likely benign	TTN-related disorder	2022-07-07	no assertion criteria provided	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).