ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.11254+2T>C (rs199565715)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare 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 (; 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 RCV000155005 SCV000237027 uncertain significance not specified 2016-06-02 criteria provided, single submitter clinical testing The c.10741+2 T>C variant of uncertain significance was identified in one individual from a cohort of 172 women diagnosed with peripartum cardiomoypathy (Ware et al., 2016). Nevertheless, this variant has been observed in a relatively high frequency among individuals in the general population. The 1000 Genomes Project, NHLBI Exome Sequencing Project, and the Exome Aggregation Consortium report that c.10741+2 T>C was observed in 0.23-0.44% of alleles from individuals of African American background, indicating it may be a rare benign variant in this population. Although the c.10741+2 T>C variant may destroy the canonical splice donor site of intron 44, a deleterious splicing effect is less likely given the lack of evolutionary conservation at this nucleotide position. Moreover, the c.10741+2 T>C variant resides in an inferred transcript that includes all possible supported in-frame coding exons. The expression pattern of this transcript is unknown. This variant maps to deep intronic regions in the major cardiac titin isoforms (N2BA; NM_001256850 and N2-B; NM_003319). Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Invitae RCV000713962 SCV000261793 likely benign not provided 2018-03-29 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000155005 SCV000704242 likely benign not specified 2017-01-27 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000155005 SCV000844614 benign not specified 2019-11-07 criteria provided, single submitter clinical testing

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