Submissions for variant NM_001267550.2(TTN):c.68449C>T (p.Arg22817Ter)

dbSNP: rs371678190

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000152238	SCV000201039	likely pathogenic	Primary dilated cardiomyopathy	2015-03-19	criteria provided, single submitter	clinical testing	The p.Arg20249X variant in TTN has not been previously reported in any other fam ilies with cardiomyopathy or in large population studies. This nonsense variant leads to a premature termination codon at position 20249, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the e xons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), whe re this variant is located. In summary, although additional studies are required to fully establish its clinical significance, the Arg20249X variant is likely p athogenic.
GeneDx	RCV000184251	SCV000236873	pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); 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); This variant is associated with the following publications: (PMID: 28045975, 28255936, 22335739)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769969	SCV000901395	pathogenic	Cardiomyopathy	2017-10-27	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845462	SCV000987553	pathogenic	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV002288662	SCV002580551	pathogenic	Dilated cardiomyopathy 1G	2021-12-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002326874	SCV002627158	pathogenic	Cardiovascular phenotype	2024-03-04	criteria provided, single submitter	clinical testing	The p.R13752* pathogenic mutation (also known as c.41254C>T), located in coding exon 149 of the TTN gene, results from a C to T substitution at nucleotide position 41254. This changes the amino acid from an arginine to a stop codon within coding exon 149. 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 alteration has been reported in both sudden death and dilated cardiomyopathy (DCM) cohorts (also reported as p.R20249* (c.60745C>T) and p.R22817* (c.68449C>T)) (Franaszczyk M et al. PLoS ONE, 2017 Jan;12:e0169007; Campuzano O et al. Sports Med, 2017 Oct;47:2101-2115). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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 Jan;49:46-53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516063	SCV002962803	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg22817*) 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 (rs371678190, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with clinical features of dilated cardiomyopathy (PMID: 28045975; Invitae). ClinVar contains an entry for this variant (Variation ID: 165869). 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.