Submissions for variant NM_001267550.2(TTN):c.107800G>T (p.Gly35934Ter)

dbSNP: rs368277535

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000725043	SCV000333491	uncertain significance	not provided	2015-07-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000725043	SCV000570208	uncertain significance	not provided	2017-10-31	criteria provided, single submitter	clinical testing	The G34293X variant of uncertain significance in the TTN gene has not been reported as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In addition, G34293X is expected to result in an abnormal, truncated protein product. While other truncating variants in the TTN gene have been reported in the Human Gene Mutation Database in association with DCM (Stenson et al., 2014), these variants are all located upstream of G34293X. Furthermore, this variant is not 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). Other truncating variants in the M-band of titin, where this variant occurs, have been reported in association with an autosomal recessive early-onset myopathy with cardiomyopathy (Carmignac et al., 2007), and heterozygous parents were reportedly healthy. Moreover, other nonsense and frameshift TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012).
Invitae	RCV001227213	SCV001399561	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly35934*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with TTN-related conditions (PMID: 28449774, 31561939, 35177841). This variant is also known as p.G26869X. ClinVar contains an entry for this variant (Variation ID: 282175). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.