Submissions for variant NM_001267550.2(TTN):c.79141A>T (p.Lys26381Ter)

dbSNP: rs1131691944

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493413	SCV000583194	likely pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Reported in association with DCM in published literature (Jansen et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Nonsense 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; 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); This variant is associated with the following publications: (PMID: 22335739, 31112426)
Invitae	RCV000642795	SCV000764482	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-08-26	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 not present in population databases (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 430400). This sequence change creates a premature translational stop signal (p.Lys26381*) 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 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).
Mayo Clinic Laboratories, Mayo Clinic	RCV000493413	SCV001715750	likely pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	PVS1, PM2
Clinical Genetics, Academic Medical Center	RCV000493413	SCV001924376	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000493413	SCV001963415	likely pathogenic	not provided		no assertion criteria provided	clinical testing