Submissions for variant NM_001267550.2(TTN):c.25063+1G>A

dbSNP: rs754247415

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000550198	SCV000642866	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-02-04	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 466942). Disruption of this splice site has been observed in individual(s) with clinical features of centronuclear myopathy (PMID: 29435569). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 86 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a truncated or disrupted TTN protein. 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.
Eurofins Ntd Llc (ga)	RCV000595351	SCV000704322	uncertain significance	not provided	2016-12-30	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338656	SCV004048353	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J		criteria provided, single submitter	clinical testing	The splice donor variant c.25063+1G>A in TTN gene has been previously reported in compound heterozygous state in a 34-year old Belgian patient affected with muscle disorder (Savarese et al. 2018). This sequence change affects a donor splice site in intron 86 of the TTN gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product, but is not anticipated to result in nonsense mediated decay. The variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. This variant is present in the ExAC population database with a frequency of 0.002%. Although this is a rare truncating variant, truncating variants have been shown to be highly prevalent in the TTN gene in the general population and unaffected individuals (Akinrinade et al. 2015). However, truncating mutations in this region have also been reported to cause recessive myotubular myopathy (Ceyhan-Birsoy et al. 2013). The nucleotide change in TTN is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic