ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.97492+1G>C (rs727505319)

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Total submissions: 6
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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

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