Submissions for variant NM_001267550.2(TTN):c.46782C>A (p.Tyr15594Ter)

dbSNP: rs397517587

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000209642	SCV000063965	likely pathogenic	Primary dilated cardiomyopathy	2012-07-30	criteria provided, single submitter	clinical testing	The Tyr13026X variant in TTN has been identified by our laboratory in one indivi dual with DCM, and was not identified in large population studies. This nonsens e variant leads to a premature termination codon at position 13026, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the TTN gene is strongly associated with DCM (Herman 2012). In summary, this v ariant is likely to be pathogenic, though additional studies are required to ful ly establish its clinical significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209642	SCV000189685	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.