Submissions for variant NM_001256850.1(TTN):c.92569+1G>C (rs727505319)

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine	RCV000156861	SCV000206582	likely pathogenic	Primary dilated cardiomyopathy	2014-10-22	criteria provided, single submitter	clinical testing	The c.89788+1G>C variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the i nvariant region (+/- 1,2) of the splice consensus sequence and is predicted to c ause altered splicing leading to an abnormal or absent protein. Splice variants and other truncating variants in TTN are strongly associated with DCM, particula rly if they are located in the exons encoding for the A-band region of the prote in (Herman 2012, Pugh 2014), where this variant is located. In summary, although additional studies are required to fully establish its clinical significance, t he c.89788+1G>C variant is likely pathogenic.
GeneDx	RCV000184284	SCV000236907	pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing	The c.92569+1 G>C pathogenic variant in the TTN gene has been previously reported in two individuals with a clinical diagnosis and family history of DCM; one individual, diagnosed at 40 years of age, also had a history of atrial fibrillation and congestive heart failure, and the other individual, diagnosed at 28 years of age, also had a history of non-sustained ventricular tachycardia (Herman et al., 2012). This variant is also classified as likely pathogenic by two other clinical laboratories in ClinVar (ClinVar SCV000206582.3, SCV000542629.1; Landrum et al., 2016). This variant destroys the canonical splice donor site in intron 299 and is predicted to cause abnormal gene splicing. This variant is predicted to lead to either an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.92569+1 G>C is located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012). Furthermore, the c.92569+1 G>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae	RCV000462323	SCV000542629	pathogenic	Dilated cardiomyopathy 1G; Limb-girdle muscular dystrophy, type 2J	2018-09-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 349 of the TTN gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22335739). This variant is also known as c.92569+1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 180058). This variant is found in the A-band of this gene. Truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). Truncating variants in TTN have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute	RCV000184284	SCV000740480	pathogenic	not provided	2016-12-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	RCV000769868	SCV000901294	pathogenic	Cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000184284	SCV000928100	likely pathogenic	not provided	2018-12-03	criteria provided, single submitter	clinical testing