Submissions for variant NM_001267550.2(TTN):c.97492+1G>C

dbSNP: rs727505319

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000156861	SCV000206582	likely pathogenic	Primary dilated cardiomyopathy	2014-10-22	criteria provided, single submitter	clinical testing	The c.89788+1G>C variant in TTN has not been previously reported in individuals with cardiomyopathy or in large population studies. This variant occurs in the i nvariant region (+/- 1,2) of the splice consensus sequence and is predicted to c ause altered splicing leading to an abnormal or absent protein. Splice variants and other truncating variants in TTN are strongly associated with DCM, particula rly if they are located in the exons encoding for the A-band region of the prote in (Herman 2012, Pugh 2014), where this variant is located. In summary, although additional studies are required to fully establish its clinical significance, t he c.89788+1G>C variant is likely pathogenic.
GeneDx	RCV000184284	SCV000236907	pathogenic	not provided	2022-07-15	criteria provided, single submitter	clinical testing	Identified in multiple unrelated patients with DCM referred for genetic testing at GeneDx and in published literature (reported as c.97492+1 G>C using alternate nomenclature) (Herman et al., 2012; Fatkin et al., 2016); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 30150400, 33874732)
Invitae	RCV000462323	SCV000542629	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 349 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 individuals with dilated cardiomyopathy (PMID: 22335739). This variant is also known as c.92569+1G>C. ClinVar contains an entry for this variant (Variation ID: 180058). 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). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). Truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). For these reasons, this variant has been classified as Pathogenic.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000184284	SCV000740480	pathogenic	not provided	2016-12-05	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769868	SCV000901294	pathogenic	Cardiomyopathy	2023-05-16	criteria provided, single submitter	clinical testing
Blueprint Genetics	RCV000184284	SCV000928100	likely pathogenic	not provided	2018-12-03	criteria provided, single submitter	clinical testing
Robert's Program, Boston Children's Hospital	RCV001788053	SCV002030075	pathogenic	SUDDEN INFANT DEATH SYNDROME	2021-10-01	criteria provided, single submitter	research	We classify this variant as pathogenic using the following ACMG/AMP criteria: PVS1, PM1, PM2, PP5
Ambry Genetics	RCV002362834	SCV002662001	likely pathogenic	Cardiovascular phenotype	2023-08-11	criteria provided, single submitter	clinical testing	The c.70297+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 176 of the TTN gene. Exon 176 is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This alteration, also reported as NM_001256850.1:c.92569+1G>C, has been reported in two individuals in a dilated cardiomyopathy (DCM) cohort (Herman DS et al. N Engl J Med, 2012 Feb;366:619-28). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration disrupts the canonical splice site and is expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. While loss of function variants in TTN are present in 1-3% of the general population, truncating variants (a category that includes canonical splice site variants) in the A-band are the most common cause of DCM (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). As such, this alteration is classified as likely pathogenic.