Submissions for variant NM_001267550.2(TTN):c.52731_52732del (p.Arg17577fs)

dbSNP: rs878854315

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000227749	SCV000286710	likely pathogenic	Dilated cardiomyopathy 1G	2016-02-18	criteria provided, single submitter	clinical testing	This sequence change deletes 2 nucleotides from exon 276 of the TTN mRNA (c.52731_52732del), causing a frameshift at codon 17577. This creates a premature translational stop signal (p.Arg17577Serfs*3) and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, truncating variants in this region of TTN are likely pathogenic (PMID: 25589632). For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000627665	SCV000748665	pathogenic	not provided	2022-08-04	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378733	SCV001576370	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-05-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg17577Serfs*3) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. 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 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). ClinVar contains an entry for this variant (Variation ID: 238798). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics	RCV004678654	SCV005173494	likely pathogenic	Cardiovascular phenotype	2024-04-20	criteria provided, single submitter	clinical testing	The c.25536_25537delAG variant, located in coding exon 103 of the TTN gene, results from a deletion of two nucleotides at nucleotide positions 25536 to 25537, causing a translational frameshift with a predicted alternate stop codon (p.R8512Sfs*3). 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 also 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.