Submissions for variant NM_001267550.2(TTN):c.22633C>T (p.Arg7545Ter)

gnomAD frequency: 0.00001  dbSNP: rs764687326

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000559278	SCV000642821	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg7545*) 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 (rs764687326, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with early-onset atrial fibrillation (PMID: 30535219). ClinVar contains an entry for this variant (Variation ID: 466909). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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.
GeneDx	RCV001355451	SCV001992474	uncertain significance	not provided	2021-01-20	criteria provided, single submitter	clinical testing	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 a region of the TTN gene for which loss-of-function is not a well established mechanism of disease; Observed in an individual with early-onset atrial fibrillation, however, additional clinical information was not provided (Choi et al., 2018); This variant is associated with the following publications: (PMID: 30535219)
CeGaT Center for Human Genetics Tuebingen	RCV001355451	SCV002585842	uncertain significance	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2:Supporting
Fulgent Genetics, Fulgent Genetics	RCV002497137	SCV002806745	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-09-08	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355451	SCV001550337	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TTN p.Arg6301* variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs764687326) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 3 of 280012 chromosomes at a frequency of 0.00001071 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7108 chromosomes (freq: 0.000141) and European (non-Finnish) in 2 of 128018 chromosomes (freq: 0.000016), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), or South Asian populations. The c.18901C>T variant leads to a premature stop codon at position 6301 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the TTN gene are an established mechanism of disease in dilated cardiomyopathy (DCM), however this transcript is not highly expressed in DCM, therefore the clinical significance of this premature stop codon is not clear. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.