Submissions for variant NM_001267550.2(TTN):c.96697C>T (p.Arg32233Ter)

dbSNP: rs781171206

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184397	SCV000237022	likely pathogenic	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Reported in a patient with lower limb myopathy who harbored another nonsense TTN variant in trans (Krenn et al.,2020) and in a patient with hypertrophic cardiomyopathy (HCM) (Hathaway et al., 2021) in published literature; Identified in conjunction with additional TTN nonsense variants in patients with cardiomyopathy and arrhythmia referred for genetic testing at GeneDx, but phase and segregation data are limited or absent at this time; 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 the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (Herman et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33673806, 35177841, 31407473, 22335739)
Invitae	RCV001852398	SCV002284887	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg32233*) 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 present in population databases (rs781171206, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive myopathy and/or hypertrophic cardiomyopathy (PMID: 31407473, 33673806). ClinVar contains an entry for this variant (Variation ID: 202528). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002362952	SCV002663664	likely pathogenic	Cardiovascular phenotype	2022-10-31	criteria provided, single submitter	clinical testing	The p.R23168* variant (also known as c.69502C>T), located in coding exon 174 of the TTN gene, results from a C to T substitution at nucleotide position 69502. This changes the amino acid from an arginine to a stop codon within coding exon 174. This exon 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, 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). As such, this alteration is classified as likely pathogenic.