Submissions for variant NM_001267550.2(TTN):c.69217_69218del (p.Lys23073fs)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Clinical Genomics Laboratory, Stanford Medicine	RCV004551162	SCV005043330	likely pathogenic	Dilated cardiomyopathy 1G	2021-07-13	criteria provided, single submitter	clinical testing	Thep.Lys23073Valfs*5variant in the TTN gene has not been previously reported in association with disease.•This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). The p.Lys23073Valfs*5 variantresults in a 2 bp deletion in exon 324 of 363 exons, which causes a shift in the protein reading frame, leading to a premature termination codon 5 amino acids downstream; however, premature termination at this location ofthe gene may not undergo nonsense-mediated decay, increasing the likelihood of an expressed protein.This variant is located in the A-band of the titin protein. Loss-of-function variants in the A-band have a known association with dilated cardiomyopathy (Morales et al., 2021).These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify thep.Lys23073Valfs*5 variant as likely pathogenic forTTN-related dilated cardiomyopathy in an autosomal dominant manner based on the information above. [ACMG evidence codes used: PVS1_Strong; PM2]