Submissions for variant NM_001267550.2(TTN):c.12016_12019dup (p.Gly4007fs)

gnomAD frequency: 0.00001  dbSNP: rs1553940935

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000599233	SCV000710123	uncertain significance	not specified	2017-11-20	criteria provided, single submitter	clinical testing	The c.11065_11068dupAGTG variant of uncertain significance in the TTN gene (also reported as c.12016_12019dupAGTG in transcript NM_001267550.1) has been identified previously in two related individuals with DCM (Jansweijer et al., 2017). This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The c.11065_11068dupAGTG variant causes a shift in reading frame starting at codon glycine 3690, changing it to a glutamic acid, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Gly3690GlufsX7. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Nevertheless, other truncating TTN variants have been reported in approximately 3% of control alleles, and the c.11065_11068dupAGTG variant is not located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696708	SCV000825282	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly4007Glufs*7) 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 0.007%). This variant has not been observed in the literature in individuals with autosomal recessive TTN-related conditions. This variant has been reported in individual(s) with dilated cardiomyopathy (PMID: 27813223, 31112426); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 503826). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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.
Clinical Genetics, Academic Medical Center	RCV001700231	SCV001921898	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700231	SCV001953231	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001700231	SCV001967099	likely pathogenic	not provided		no assertion criteria provided	clinical testing