Submissions for variant NM_001267550.2(TTN):c.67166_67167del (p.Tyr22389fs)

dbSNP: rs1476017129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000540750	SCV000642455	likely pathogenic	Dilated cardiomyopathy 1G	2017-06-03	criteria provided, single submitter	clinical testing	This sequence change deletes 2 nucleotide from exon 318 of the TTN mRNA (c.67166_67167delAT), causing a frameshift at codon 22389. This sequence change creates a premature translational stop signal (p.Tyr22389Cysfs*6) in the TTN gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant is found in the A-band of this gene. While this particular variant has not been reported in the literature, truncating variants in the A-band of TTN are significantly overrepresented in patients with dilated cardiomyopathy and are considered to be likely pathogenic for the disease (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
Invitae	RCV001378833	SCV001576501	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr22389Cysfs*6) 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 466652). 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223865	SCV002502876	likely pathogenic	not provided	2022-02-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002476154	SCV002793257	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	2021-10-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527643	SCV004104230	likely pathogenic	TTN-related disorder	2023-01-23	criteria provided, single submitter	clinical testing	The TTN c.67166_67167delAT variant is predicted to result in a frameshift and premature protein termination (p.Tyr22389Cysfs*6). To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is located in the A-band region of the protein in which truncating TTN variants have been found more frequently in dilated cardiomyopathy patients than in controls (Herman et al. 2012. PubMed ID: 22335739). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 92-100%); however, this analysis in muscle tissue was not performed (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts A.M. et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). This variant is considered likely pathogenic for increased risk of TTN-related cardiac disorders, and also for autosomal recessive severe congenital titinopathies when in the presence of an additional loss-of-function TTN variant. Of note, TTN truncating variants show incomplete and age-dependent penetrance in regards to autosomal dominant dilated cardiomyopathy. ACMG has recommended the reporting of TTN truncating variants in highly expressed exons due to the significant risk of cardiomyopathy (see ACMG statement in Miller et al. 2021. PubMed ID: 34012068).
Ambry Genetics	RCV004024027	SCV005020569	likely pathogenic	Cardiovascular phenotype	2024-01-02	criteria provided, single submitter	clinical testing	The c.39971_39972delAT variant, located in coding exon 145 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 39971 to 39972, causing a translational frameshift with a predicted alternate stop codon (p.Y13324Cfs*6). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic.