Submissions for variant NM_001267550.2(TTN):c.47479C>T (p.Gln15827Ter)

dbSNP: rs794729261

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184217	SCV000236839	pathogenic	not provided	2017-03-01	criteria provided, single submitter	clinical testing	The Q14186X variant in the TTN gene has not been reported as a disease-causing variant or as a benign polymorphism to our knowledge. Q14186X is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman D et al., 2012). However, Q14186X is located in the A-band region of titin, where the majority of truncating variants associated with DCM have been reported (Herman D et al., 2012). Furthermore, the Q14186X variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.In summary, Q14186X in the TTN gene is interpreted as a disease-causing mutation.
Mayo Clinic Laboratories, Mayo Clinic	RCV000184217	SCV004226735	likely pathogenic	not provided	2022-06-30	criteria provided, single submitter	clinical testing	PM2_supporting, PVS1
Labcorp Genetics (formerly Invitae), Labcorp	RCV005222808	SCV005864334	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-12-12	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln15827*) 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 autosomal dominant dilated cardiomyopathy (internal data). ClinVar contains an entry for this variant (Variation ID: 202370). 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.