Submissions for variant NM_001267550.2(TTN):c.83653G>T (p.Glu27885Ter)

dbSNP: rs794729295

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184274	SCV000236897	likely pathogenic	not provided	2012-12-04	criteria provided, single submitter	clinical testing	p.Glu26244Stop (GAG>TAG): c.78730 G>T in exon 276 of the TTN gene (NM_001256850.1). The Glu26244Stop variant in the TTN gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Glu26244Stop is predicted to cause loss of normal protein function either due to production of an abnormal, prematurely truncated protein, or by absence of protein product due to nonsense mediated mRNA decay. Glu26244Stop is located in the A-band region of titin, where the majority of truncating mutations associated with DCM have been reported (Herman D et al., 2012). In addition, the NHLBI ESP Exome Variant Server reports Glu26244Stop was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations.In summary, while the Glu26244Stop variant in the TTN gene is likely a disease-causing mutation, the possibility it is a rare benign variant cannot be excluded. The variant is found in DCM panel(s).
Invitae	RCV003765148	SCV004604312	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Glu27885*) 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: 202418). 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.