Submissions for variant NM_001267550.2(TTN):c.103705A>T (p.Lys34569Ter)

dbSNP: rs1553490574

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000592204	SCV000705238	likely pathogenic	not provided	2017-01-16	criteria provided, single submitter	clinical testing
Invitae	RCV001217365	SCV001389201	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.Lys34569*) 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 individual(s) with dilated cardiomyopathy (PMID: 36264615). ClinVar contains an entry for this variant (Variation ID: 499641). 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). 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.
Revvity Omics, Revvity	RCV000592204	SCV002021459	likely pathogenic	not provided	2020-04-07	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV002260514	SCV002540247	likely pathogenic	Dilated cardiomyopathy 1G	2022-01-19	criteria provided, single submitter	clinical testing	The TTN c.103705A>T (p.Lys34569Ter) nonsense variant results in the substitution of lysine at amino acid position 34569 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant is in the M-band in an exon that is highly expressed cardiac tissue (Roberts et al. 2015). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with an increased risk of developing DCM and related cardiovascular phenotypes (odds ratio 3.7) (Schafer et al. 2017). To our knowledge, this variant has not been reported in the peer-reviewed literature. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Based on the available evidence, the c.103705A>T (p.Lys34569Ter) variant is classified as likely pathogenic for dilated cardiomyopathy.
Ambry Genetics	RCV002395527	SCV002671788	likely pathogenic	Cardiovascular phenotype	2022-10-12	criteria provided, single submitter	clinical testing	The p.K25504* variant (also known as c.76510A>T), located in coding exon 185 of the TTN gene, results from an A to T substitution at nucleotide position 76510. This exon is located in the M-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). 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 M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.