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
Invitae	RCV001050674	SCV001214793	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-13	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). 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 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	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.