Submissions for variant NM_001267550.2(TTN):c.55432+5G>C

gnomAD frequency: 0.00001  dbSNP: rs754717390

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184239	SCV000236861	pathogenic	not provided	2014-05-12	criteria provided, single submitter	clinical testing	c.50509+5 G>C: IVS236+5 G>C in intron 236 of the TTN gene (NM_001256850.1). Although the c.50509+5 G>C mutation in the TTN gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge, this mutation destroys the canonical splice donor site in intron 236 and is predicted to cause abnormal gene splicing. Other splice site mutations in the TTN gene have been reported in association with cardiomyopathy. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.50509+5 G>C is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012).In summary, c.50509+5 G>C in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Laboratory Services, Illumina	RCV000331273	SCV000422755	uncertain significance	Hypertrophic cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000385626	SCV000422756	uncertain significance	Dilated Cardiomyopathy, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000295999	SCV000422757	uncertain significance	Myopathy, myofibrillar, 9, with early respiratory failure	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000350933	SCV000422758	uncertain significance	Tibial muscular dystrophy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000405475	SCV000422759	uncertain significance	Early-onset myopathy with fatal cardiomyopathy	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000278169	SCV000422760	uncertain significance	Limb-Girdle Muscular Dystrophy, Recessive	2016-06-14	criteria provided, single submitter	clinical testing
Invitae	RCV000546209	SCV000643381	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change falls in intron 286 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs754717390, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy or left ventricular noncompaction and hypertrophic cardiomyopathy (PMID: 28822653; Invitae). ClinVar contains an entry for this variant (Variation ID: 202391). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 A band of TTN (PMID: 25589632). Variants in this region may be relevant for cardiac or neuromuscular disorders (PMID: 25589632, 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.
Ambry Genetics	RCV003165414	SCV003860969	uncertain significance	Cardiovascular phenotype	2023-01-13	criteria provided, single submitter	clinical testing	The c.28237+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 113 in the TTN gene. This variant (referred to as c.G55432+5C) co-occurred with an MYBPC3 nonsense variant in an individual from a hypertrophic cardiomyopathy cohort, and was also detected in a control individual from the same study (Zhang C et al. Can J Cardiol, 2017 Oct;33:1292-1297). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GenomeConnect, ClinGen	RCV001249326	SCV001423292	not provided	Dilated cardiomyopathy 1G; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 06-14-2019 by Lab or GTR ID 500188. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.