Submissions for variant NM_001267550.2(TTN):c.36402del (p.Val12135fs)

dbSNP: rs1271664419

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001767749	SCV001999527	likely pathogenic	not provided	2024-10-24	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 a region of TTN in which the majority of pathogenic variants have been reported in association with autosomal recessive titinopathies (PMID: 28040389, 29575618, 31660661, 32778822); This variant is associated with the following publications: (PMID: 28040389, 29575618, 31660661, 32778822)
AiLife Diagnostics, AiLife Diagnostics	RCV001767749	SCV002503126	uncertain significance	not provided	2021-12-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV005225476	SCV005862283	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-06-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Val12135Cysfs*23) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 1310635). 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, Invitae 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, Invitae 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.