Submissions for variant NM_001267550.2(TTN):c.68641C>T (p.Arg22881Ter)

dbSNP: rs1213930919

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000578155	SCV000680031	likely pathogenic	Hypertrophic cardiomyopathy 9	2017-09-19	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_003319.4(TTN):c.41446C>T, has been identified in exon 151 of 191 of the TTN gene. The variant is predicted to result in a premature stop codon at position 13816 of the protein (NP_003310.4(TTN):p.(Arg13816*). This variant is predicted to result in loss of protein function either through truncation (>50% of the protein, including multiple conserved domains) or nonsense-mediated decay. Exon 151 is expressed in the majority of cardiac transcripts (PSI=0.91). Truncating variants in exons expressed in the majority of cardiac transcripts (PSI>0.9) have been reported to be significantly associated with dilated cardiomyopathy (Roberts et al 2015 and Shafer et al 2016). The variant is absent in population databases (gnomAD, dbSNP, 1000G) and has not been previously reported in clinical cases. Based on the information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001039553	SCV001203085	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg22881*) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 488396). 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	RCV002330994	SCV002628930	likely pathogenic	Cardiovascular phenotype	2024-12-10	criteria provided, single submitter	clinical testing	The p.R13816* variant (also known as c.41446C>T), located in coding exon 150 of the TTN gene, results from a C to T substitution at nucleotide position 41446. This changes the amino acid from an arginine to a stop codon within coding exon 150. 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 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.
GeneDx	RCV003332208	SCV004039717	likely pathogenic	not provided	2023-06-27	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; 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); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22335739)
CeGaT Center for Human Genetics Tuebingen	RCV003332208	SCV005092227	likely pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796238	SCV005417042	likely pathogenic	Dilated cardiomyopathy 1G		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1