Submissions for variant NM_001267550.2(TTN):c.89270del (p.Lys29757fs)

dbSNP: rs794729362

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184355	SCV000236980	pathogenic	not provided	2012-11-30	criteria provided, single submitter	clinical testing	c.81566delA: p.Lys27189SerfsX17 (K27189SfsX17) in exon 283 of the TTN gene (NM_133378.4). The normal sequence with the base that is deleted in braces is: AGTA{A}GCCT. Although the c.81566delA mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Lysine 27189, changing it to a Serine, and creating a premature stop codon at position 17 of the new reading frame, denoted p.Lys27189SerfsX17. This mutation is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Another nearby frameshift mutation in the same fibronectin domain of the titin protein has been reported in association with DCM which causes a similar protein effect (c.82381delG, or p.Glu27461LysfsX11) (Gerull B et al., 2006). In summary, c.81566delA in the TTN gene is interpreted as a disease-causing mutation. The variant is found in DCM panel(s).
Invitae	RCV003765152	SCV004594062	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-04-22	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 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: 202490). 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.Lys29757Serfs*17) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.