Submissions for variant NM_001267550.2(TTN):c.107377+1G>C

dbSNP: rs112188483

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001221534	SCV001393586	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 361 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy (PMID: 28716623, 29382405, 29435569). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.99673+1G>C. ClinVar contains an entry for this variant (Variation ID: 949939). 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 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). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity	RCV001780146	SCV002021484	likely pathogenic	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001780146	SCV002770599	pathogenic	not provided	2022-03-16	criteria provided, single submitter	clinical testing	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with myopathy and a second truncating variant in the TTN gene (PMID: 29382405). This variant occurs in the M-band of the TTN gene, and is a canonical splice site variant in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). A different canonical splice site variant at this position (c.107377+1G>A) has been reported in combination with a second truncating variant in TTN in multiple individuals with muscular dystrophy and dilated cardiomyopathy, as well as heterozygous in apparently asymptomatic individuals (PMID: 25589632, 28716623, 29435569, 34135346). Truncating variants in the TTN gene occur significantly more often in the M-band of muscular dystrophy patients, and in the A-band of cardiomyopathy patients, compared to the general population (PMID: 255289632).
Fulgent Genetics, Fulgent Genetics	RCV002504278	SCV002814482	likely pathogenic	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	2021-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001780146	SCV003761989	pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Identified in a patient with teenage-onset myalgia, recurrent rhabdomyolysis, progressive proximal weakness, atrial fibrillation, and congestive heart failure in published literature (Wu et al., 2018); this individual harbored an additional variant in the TTN gene; Not observed at significant frequency in large population cohorts (gnomAD); Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17444505, 29382405)