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

dbSNP: rs878854315

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	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)
Invitae	RCV001378733	SCV001576370	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-05-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 238798). 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). 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). 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.