Submissions for variant NM_001267550.2(TTN):c.56853del (p.Gly18952fs)

dbSNP: rs794729392

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000184409	SCV000237034	pathogenic	not provided	2014-11-19	criteria provided, single submitter	clinical testing	c.51930delT: p.Gly17311ValfsX46 (G17311VfsX46) in exon 241 of the TTN gene (NM_001256850.1). Although the c.51930delT mutation in the TTN gene has not been reported to our knowledge, this mutation causes a shift in reading frame starting at codon Glycine 17311, changing it to a Valine, and creating a premature stop codon at position 46 of the new reading frame, denoted p.Gly17311ValfsX46. 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. Although, truncating variants in the TTN gene have been reported in approximately 3% of reported control alleles, this variant is located in the A-band region of titin, where the majority of mutations associated with DCM have been reported (Herman D et al., 2012). Furthermore, the c.51930delT mutation was not observed in approximately 6,000 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, c.51930delT in the TTN gene is interpreted as a disease-causing mutation. The variant is found in CARDIOMYOPATHY panel(s).
Invitae	RCV001852401	SCV002306895	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-05-14	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: 202539). This variant is also known as p.Gly17311ValfsX46. This premature translational stop signal has been observed in individual(s) with atrial fibrillation and/or dilated cardiomyopathy (PMID: 31638414, 34315225). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gly18952Valfs*46) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.