Submissions for variant NM_001267550.2(TTN):c.98171_98174dup (p.Ile32726fs)

dbSNP: rs1275153634

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001218658	SCV001390551	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-04-21	criteria provided, single submitter	clinical testing	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. This sequence change creates a premature translational stop signal (p.Ile32726Tyrfs*13) 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 (no rsID available, gnomAD 0.003%). 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: 947556). 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).
GeneDx	RCV002267085	SCV002549259	likely pathogenic	not provided	2022-06-27	criteria provided, single submitter	clinical testing	Frameshift 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); Has not been previously published as pathogenic or benign to our knowledge; 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: 22335739)
Ambry Genetics	RCV002365991	SCV002663899	likely pathogenic	Cardiovascular phenotype	2022-04-29	criteria provided, single submitter	clinical testing	The c.70976_70979dupTTAC variant, located in coding exon 179 of the TTN gene, results from a duplication of TTAC at nucleotide position 70976, causing a translational frameshift with a predicted alternate stop codon (p.I23661Yfs*13). 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 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 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). As such, this alteration is classified as likely pathogenic.
Athena Diagnostics Inc	RCV002267085	SCV004229412	uncertain significance	not provided	2023-01-16	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant is predicted to result in premature termination and the loss of a functional protein in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). This variant is in the TTN A-band. Premature termination variants that occur in this region are enriched in cardiomyopathy patients compared to the general population (PMID: 31849696), while their significance for muscular dystrophy is uncertain. Premature termination variants in the TTN gene have also been found in healthy individuals (PMID: 25589632).