Submissions for variant NM_001267550.2(TTN):c.32471-1G>A

gnomAD frequency: 0.00001  dbSNP: rs371725574

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000174435	SCV000225736	uncertain significance	not provided	2017-04-19	criteria provided, single submitter	clinical testing
Invitae	RCV001060586	SCV001225286	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 129 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 27854218, 35177841, 36264615). ClinVar contains an entry for this variant (Variation ID: 194146). 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, Invitae 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, Invitae 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	RCV000174435	SCV001989056	uncertain significance	not provided	2023-11-03	criteria provided, single submitter	clinical testing	Reported as c.32471-1G>A, due to the use of alternate nomenclature, in an individual with a suspected familial titinopathy who harbored a second TTN variant (PMID: 27854218); Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 35177841, 27854218, 33226272, 36937954)
AiLife Diagnostics, AiLife Diagnostics	RCV000174435	SCV002501878	uncertain significance	not provided	2021-08-09	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500468	SCV002814156	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	2022-04-26	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989491	SCV004807743	uncertain significance	Dilated cardiomyopathy 1G	2024-03-29	criteria provided, single submitter	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000723286	SCV000854675	likely pathogenic	Tibial muscular dystrophy	2018-05-08	no assertion criteria provided	clinical testing