Submissions for variant NM_001267550.2(TTN):c.34930+2T>C

gnomAD frequency: 0.00004  dbSNP: rs749252830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000597258	SCV000708687	uncertain significance	not provided	2017-06-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001050674	SCV001214793	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 154 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is present in population databases (rs749252830, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with atrial fibrillation (PMID: 30535219, 35177841). This variant has been reported in individual(s) with autosomal dominant dilated cardiomyopathy (internal data); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 502085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, internal data). 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, internal data). 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	RCV000597258	SCV001820453	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	Identified in an individual with early-onset atrial fibrillation as well as in an individual with left ventricular noncompaction who also harbored a truncation variant in RBM20 (Miszalski-Jamka et al., 2017; Choi et al., 2018); Canonical splice site variant in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 28798025, 35177841, 30535219, 27625338, 27869827)
AiLife Diagnostics, AiLife Diagnostics	RCV000597258	SCV002501262	uncertain significance	not provided	2022-01-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000597258	SCV003822987	uncertain significance	not provided	2019-11-21	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001535718	SCV001749807	not provided	Primary dilated cardiomyopathy; Myopathy, centronuclear, 2; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-04-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.