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

gnomAD frequency: 0.00002  dbSNP: rs112188483

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000209587	SCV000189713	likely pathogenic	Primary dilated cardiomyopathy	2014-10-08	criteria provided, single submitter	research	This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart.
Eurofins Ntd Llc (ga)	RCV000413060	SCV000229482	pathogenic	not provided	2018-08-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000413060	SCV000491354	pathogenic	not provided	2023-04-07	criteria provided, single submitter	clinical testing	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; Published functional analysis demonstrates that this variant alters normal gene transcription and expression (Harris et al., 2017); Observed in multiple unrelated individuals with neuromuscular disease who harbor a second TTN variant (Harris et al., 2017; Savarese et al., 2018), and in an individual with dilated cardiomyopathy who did not harbor a second TTN variant (Roberts et al., 2015); 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); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32778822, 25589632, 25214167, 32039858, 34135346, 28716623, 35177841, 35081925, 17444505, 29435569)
Athena Diagnostics	RCV000413060	SCV000615984	pathogenic	not provided	2016-09-06	criteria provided, single submitter	clinical testing
Invitae	RCV000797446	SCV000937003	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 361 of the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. This variant is present in population databases (rs112188483, gnomAD 0.007%). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 25214167, 25589632, 28716623, 36264615). 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. ClinVar contains an entry for this variant (Variation ID: 196723). 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
AiLife Diagnostics, AiLife Diagnostics	RCV000413060	SCV002502472	pathogenic	not provided	2021-10-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485159	SCV002801277	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	2021-09-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000413060	SCV003819075	uncertain significance	not provided	2019-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003380504	SCV004092465	pathogenic	Cardiovascular phenotype	2023-07-18	criteria provided, single submitter	clinical testing	The c.80182+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 188 of the TTN gene. Coding exon 188 is located in the M-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 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 variant (also referred to as NM_001267550.1:c.107377+1G>A) has been reported to co-occur in trans and with phase unknown with other TTN truncating variants in unrelated and related individuals with skeletal myopathies with or without cardiac involvement and an individual from a dilated cardiomyopathy cohort (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017; Savarese M et al. JAMA Neurol, 2018 May;75:557-565; Savarese M et al. Genet Med, 2020 Dec;22:2029-2040). Functional studies have also indicated this variant to result in aberrant splicing (Harris E et al. Neuromuscul Disord, 2017 Nov;27:1009-1017). 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Mayo Clinic Laboratories, Mayo Clinic	RCV000413060	SCV004225980	pathogenic	not provided	2022-12-22	criteria provided, single submitter	clinical testing	PP1, PM3_strong, PVS1
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017452	SCV004847677	pathogenic	Neuromuscular disease	2019-04-12	criteria provided, single submitter	clinical testing	The c.99673+1G>A variant in TTN, reported in the literature as c.107377+1G>A (NM_001267550.1), has been identified in the compound heterozygous state with truncating A-band variants in 3 individuals with limb girdle muscular dystrophy (LGMD) and 1 individual with mild progressive muscle weakness and dilated cardiomyopathy (DCM) and segregated with disease in 1 affected sibling. The heterozygous parents of these individuals were all reportedly unaffected (Harris 2017, Savarese 2018). It has been reported in the heterozygous state in 1 individual with DCM (Roberts 2015). It has also been identified in 3/248508 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 196723). This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. In addition, cDNA and Western blot analysis of patient cells demonstrated an impact to splicing (Harris 2017, Savarese 2018). Based on the available evidence, it is not clear if this variant is causative of autosomal dominant DCM, which is usually associated with truncating variants in the A-band. However, this variant meets criteria to be classified as pathogenic for autosomal recessive LGMD. ACMG/AMP criteria applied: PM3_Strong, PM2, PVS1_Moderate, PP1, PS3_Supporting.