Submissions for variant NM_001267550.2(TTN):c.85510G>T (p.Glu28504Ter)

dbSNP: rs876657670

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000213508	SCV000271283	likely pathogenic	Primary dilated cardiomyopathy	2020-12-09	criteria provided, single submitter	clinical testing	The p.Glu25936X variant in TTN has not been previously reported in individuals with TTN-related disorders, such as dilated cardiomyopathy and neuromuscular conditions and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 25936, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are strongly associated with DCM, particularly if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Glu25936X variant is located in the A-band in the highly expressed exon 275. In summary, although additional studies are required to fully establish its clinical significance, the p.Glu25936X variant is likely pathogenic for autosomal dominant dilated cardiomyopathy. ACMG/AMP criteria applied: PVS1, PM2.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769913	SCV000901339	likely pathogenic	Cardiomyopathy	2019-11-19	criteria provided, single submitter	clinical testing