Submissions for variant NM_001267550.2(TTN):c.107644del (p.Ser35882fs)

dbSNP: rs1179955071

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000733859	SCV000861961	likely pathogenic	not provided	2018-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001047430	SCV001211391	likely pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-12-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser35882Alafs*11) 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 present in population databases (no rsID available, gnomAD 0.0009%). 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: 597673). 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), but have not been definitively shown to cause cardiomyopathy (PMID: 25589632). 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.
Genetic Services Laboratory, University of Chicago	RCV000733859	SCV002064392	likely pathogenic	not provided	2020-07-07	criteria provided, single submitter	clinical testing	This variant results in an amino acid frameshift and creates a premature stop codon 10 amino acids downstream of the change, p.Ser33314Alafs*11. This variant is predicted to result in an abnormal transcript and the production of a truncated TTN protein with potentially abnormal function. This variant has been described in the gnomAD database in one individual, with a low overall population frequency of 0.0004% (dbSNP rs1179955071). This variant occurs in the M band of the TTN protein, where other truncating variants have been described in individuals with autosomal recessive myopathy and muscular dystrophy (PMIDs: 18948003, 23975875, 24395473). Bi-allelic truncating variants have been described in individuals with distal tibial muscular dystrophy (PMID 27796757, 24395473, 18948003).
PreventionGenetics, part of Exact Sciences	RCV004535873	SCV004107289	likely pathogenic	TTN-related disorder	2023-07-20	criteria provided, single submitter	clinical testing	The TTN c.107644delA variant is predicted to result in a frameshift and premature protein termination (p.Ser35882Alafs*11). This variant occurs in exon 362 which is located in the M-band region of the TTN protein. Exons 358-363 (Mex1-Mex6) have historically been found to harbor a significant number of pathogenic variants for TTN-related autosomal dominant and recessive muscle disorders (Hackman et al. 2002. PMID: 12145747; Evilä et al. 2014. PMID: 24395473). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts et al. 2015. PMID: 25589632; Herman et al. 2012. PMID: 22335739). Many cases of recessive congenital TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy et al. 2013. PMID: 23975875; Chauveau et al. 2014. PMID: 24105469; Evilä et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179392208-CT-C). Frameshift variants in TTN are expected to be pathogenic. This variant is interpreted as likely pathogenic.
GeneDx	RCV000733859	SCV005392276	likely pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in abnormal protein length as the last 110 amino acids are replaced with 10 different amino acids, and other similar variants have been reported in HGMD; Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (PMID: 17444505); This variant is associated with the following publications: (PMID: 17444505)