Submissions for variant NM_001267550.2(TTN):c.101107C>T (p.Arg33703Ter)

gnomAD frequency: 0.00001  dbSNP: rs766265889

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Petrovsky National Research Centre of Surgery, The Federal Agency for Scientific Organizations	RCV000766232	SCV000891776	likely pathogenic	Dilated cardiomyopathy 1G	2019-03-22	criteria provided, single submitter	research	We observed NM_001267550.2:c.101107C>T (p.Arg33703*) variant in male proband and proband's mother, both diagnosed with DCM. The c.101107C>T (p.Arg33703*) variant is, to our knowledge, very rare (MAF- 0.00001797 in the gnomAD). It is also a truncating variant located in constitutively expressed exon (PVS1 interpretation criteria). Based on this evidence and on family segregation data, we classify c.101107C>T (p.Arg33703*) variant as likely pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769860	SCV000901286	likely pathogenic	Cardiomyopathy	2017-01-05	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000821045	SCV000961786	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-08-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg33703*) 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 (rs766265889, gnomAD 0.002%). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive TTN-related conditions and/or dilated cardiomyopathy (PMID: 31712709, 31931689, 36264615; Invitae). ClinVar contains an entry for this variant (Variation ID: 625156). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485976	SCV002776519	likely 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	2021-11-24	criteria provided, single submitter	clinical testing
Molecular Genetics, Royal Melbourne Hospital	RCV003994109	SCV004812349	likely pathogenic	Primary dilated cardiomyopathy	2023-09-04	criteria provided, single submitter	clinical testing	This sequence change in TTN is a nonsense variant predicted to cause a premature stop codon, p.(Arg33703*), in constitutively expressed exon 358 (percentage splice in, PSI, 100%) in the M-band. High PSI truncating variants in TTN have a significant association with dilated cardiomyopathy (PMID: 31216868). The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/112,638 alleles) in the European (non-Finnish) population. This variant has been reported in multiple individuals with cardiomyopathy and has been reported to segregate in one family (PMID:31712709, 31931689; CHEO Diagnostic, Invitae). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PVS1_Strong, PM2_Supporting, PS4_Moderate.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV003994109	SCV004847683	likely pathogenic	Primary dilated cardiomyopathy	2019-04-12	criteria provided, single submitter	clinical testing	The p.Arg31135X variant in TTN has not been reported in individuals with TTN-associated diseases, such as dilated cardiomyopathy and neuromuscular conditions but has been identified in 2/112638 of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 31135, which is predicted to lead to a truncated or absent protein. TTN truncating variants located in exons that are highly expressed in the heart are strongly associated with autosomal dominant DCM, particularly if they are located in the A-band (Herman 2012, Pugh 2014, Roberts 2015). In addition, TTN variants have also been associated with myopathies and other neuromuscular conditions, which usually have autosomal recessive inheritance (Savarese 2016). The p.Arg31135X variant is located in a highly expressed exon in the M-band. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for TTN-associated diseases. ACMG/AMP Criteria applied: PVS1, PM2.