Submissions for variant NM_001267550.2(TTN):c.106015del (p.Asp35339fs)

dbSNP: rs1558988204

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768819	SCV000900192	uncertain significance	Cardiomyopathy	2020-06-29	criteria provided, single submitter	clinical testing
Invitae	RCV001231179	SCV001403690	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-12-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp35339Metfs*66) 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: 626393). This variant is located in the M band of TTN (PMID: 25589632). Truncating variants in this region have been previously reported in individuals affected with autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742). 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003336174	SCV004046098	likely pathogenic	TTN-Related Disorders		criteria provided, single submitter	clinical testing	This frameshifting variant in exon 358 of 363 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has not been previously reported or functionally characterized in the literature to our knowledge. This variant is located in the M-band of TTN (PMID: 25589632). Frameshift variants in the TTN gene have been reported in the databases (Human Gene Mutation Database, ClinVar) in association with cardiomyopathy, with majority of these variants located in the A-band region of TTN (PMID: 22335739). However, majority of truncating variants in the M-band of TTN have been previously reported in affected individuals with various forms of autosomal recessive myopathy and muscular dystrophy (PMID: 18948003, 23975875, 24395473). The c.106015del (p.Asp35339MetfsTer66) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.106015del (p.Asp35339MetfsTer66) variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV003884723	SCV004699088	likely pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing	TTN: PVS1:Strong, PM2