Submissions for variant NM_001267550.2(TTN):c.99874del (p.Asp33292fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003236316	SCV003934132	pathogenic	Primary familial dilated cardiomyopathy	2023-05-23	criteria provided, single submitter	clinical testing	Variant summary: TTN c.92170delG (p.Asp30724ThrfsX8) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 239476 control chromosomes. To our knowledge, no occurrence of c.92170delG in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Frameshift and other truncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (PMID: 22335739, PMID: 24503780). Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003779858	SCV004604395	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp33292Thrfs*8) 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: 2506085). 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.