Submissions for variant NM_001267550.2(TTN):c.45307C>T (p.Arg15103Ter)

gnomAD frequency: 0.00001  dbSNP: rs397517580

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000040256	SCV000063947	likely pathogenic	Primary dilated cardiomyopathy	2017-08-25	criteria provided, single submitter	clinical testing	The p.Arg12535X variant in TTN has been identified by our laboratory in 1 indivi dual with DCM and segregated with disease in 2 affected relatives, including one obligate carrier. This variant was absent from large population studies. This n onsense variant leads to a premature termination codon at position 12535, which is predicted to lead to a truncated or absent protein. Nonsense and other trunca ting variants in TTN are strongly associated with DCM if they impact the exons e ncoding the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that i s highly expressed in the heart (Roberts 2015). The p.Arg12535X variant is locat ed in the I-band in the highly expressed exon 194. In summary, although addition al studies are required to fully establish its clinical significance, the p.Arg1 2535X variant is likely pathogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000642772	SCV000764459	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg15103*) in 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with clinical features of centronuclear myopathy and/or dilated cardiomyopathy (PMID: 27532257, 31251381, 31727422, 31983221; Invitae). This variant is also known as p.Arg12535Ter. ClinVar contains an entry for this variant (Variation ID: 46986). 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). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000786251	SCV001811436	likely pathogenic	not provided	2023-08-10	criteria provided, single submitter	clinical testing	Reported in association with cardiomyopathy and sudden death (Pugh et al., 2014; Walsh et al., 2017; Corden et al., 2019; Khera et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 31983221, 31727422, 27532257, 27625338, 27869827, 35177841, 31251381, 24503780)
Mayo Clinic Laboratories, Mayo Clinic	RCV000786251	SCV002103201	likely pathogenic	not provided	2021-11-30	criteria provided, single submitter	clinical testing	PM2
Ambry Genetics	RCV002408529	SCV002713243	likely pathogenic	Cardiovascular phenotype	2024-05-07	criteria provided, single submitter	clinical testing	The p.R6038* variant (also known as c.18112C>T), located in coding exon 72 of the TTN gene, results from a C to T substitution at nucleotide position 18112. This changes the amino acid from an arginine to a stop codon within coding exon 72. This exon is located in the I-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 was reported in one individual with dilated cardiomyopathy (DCM) (Pugh TJ et al. Genet. Med., 2014 Aug;16:601-8). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the A-band are the most common cause of dilated cardiomyopathy (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). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is classified as likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000786251	SCV000925001	uncertain significance	not provided	2017-09-22	no assertion criteria provided	provider interpretation