Submissions for variant NM_001267550.2(TTN):c.10592C>G (p.Ser3531Ter)

gnomAD frequency: 0.00001  dbSNP: rs767420661

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209078	SCV000189747	uncertain significance	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 with low levels of cardiac expression. 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.
Invitae	RCV000464802	SCV000542761	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-07-17	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser3531*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs767420661, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 25589632). ClinVar contains an entry for this variant (Variation ID: 223345). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV001731524	SCV001983229	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing	Reported in an individual with dilated cardiomyopathy, however, detailed clinical and segregation information were not included (Roberts et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in the I-band region of the TTN gene, which is not one of the regions known to be significantly associated with TTN-related disease; Present in an alternate meta-transcript which contains all possible coding exons of the TTN gene (NM_001267550.1), and is not present in the coding portion of the TTN primary transcripts (NM_133378.4 and NM_001256850.1); This variant is associated with the following publications: (PMID: 25589632)