Submissions for variant NM_001267550.2(TTN):c.62597del (p.Gly20866fs)

dbSNP: rs1576066084

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001008874	SCV001168680	likely pathogenic	not provided	2018-05-22	criteria provided, single submitter	clinical testing	The c.57674delG likely pathogenic variant in the TTN gene has not been reported as pathogenic or benign to our knowledge. This variant causes a shift in reading frame starting at codon Glycine 19225, changing it to a Valine, and creating a premature stop codon at position 3 of the new reading frame, denoted p.Gly19225ValfsX3. 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. Other truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). However, c.57674delG is 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). Moreover, the c.57674delG variant has not been observed in large population cohorts (Lek et al., 2016). Nevertheless, segregation and functional study date are not available at this time to further support the pathogenicity of this variant.
Invitae	RCV001059487	SCV001224111	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-07-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly20866Valfs*3) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. 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: 817669). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency).