Submissions for variant NM_001267550.2(TTN):c.36253C>T (p.Gln12085Ter)

gnomAD frequency: 0.00004  dbSNP: rs1384922524

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002305615	SCV001772242	pathogenic	not provided	2022-09-27	criteria provided, single submitter	clinical testing	Present in an alternate meta-transcript which contains all possible coding exons of the TTN gene (NM_001267550.1), and is not present in the coding portion of the TTN primary transcripts (NM_133378.4 and NM_001256850.1); Truncating pathogenic variants located in metatranscript-only exons have been reported in association with autosomal recessive congenital titinopathies (Fernandez-Marmiesse et al., 2017; Chervinsky et al., 2018; Bryen, et al., 2020; Savarese et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Located in a region of TTN within the I-band in which the majority of loss of function variants are significantly associated with autosomal dominant titinopathies (Deo et al., 2016; Schafer et al., 2017); This variant is associated with the following publications: (PMID: 27535533, 27625338, 27869827)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797845	SCV002041808	uncertain significance	not specified	2023-09-01	criteria provided, single submitter	clinical testing	Variant summary: TTN c.31484-1432C>T is located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is also annotated as c.36253C>T (p.Q12085*) in exon 168 of the meta transcript, NM_001267550.2 of the TTN gene. This exon is not constitutively expressed and has a low PSI (percentage spliced in) score and is considered to be symmetric, i.e. the length of the exon is a multiple of three and therefore removal of it will not alter the reading frame. The variant was absent in 240998 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.31484-1432C>T in individuals affected with Limb-Girdle Muscular Dystrophy, Type 2J/Dilated Cardiomyopathy (DCM) and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001882629	SCV002199991	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2021-08-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln12085*) 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 (ExAC no frequency). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences	RCV004542003	SCV004781413	likely pathogenic	TTN-related disorder	2024-02-23	no assertion criteria provided	clinical testing	The TTN c.36253C>T variant is predicted to result in premature protein termination (p.Gln12085*). To our knowledge, this variant has not been reported in the literature. This variant is located in the TTN protein I-band region. RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (Exon 169, PSI of 2-7%%); however, this analysis was not performed in muscle tissue (Roberts et al. 2015. PMID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values (Roberts et al. 2015. PMID: 25589632; Herman D.S. et al. 2012. PMID: 22335739). This variant is found in an exon specific to the TTN meta-transcript and is not included in the skeletal muscle isoform (NM_133378.4); however, many other protein truncating and splice variants in these low PSI metatranscript-only exons have been recently observed in severe recessive congenital titinopathies (Bryen et al. 2020. PubMed ID: 31660661; Oates et al. 2018. PubMed ID: 29691892; Chervinsky et al. 2018. PubMed ID: 29575618). Many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (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 0.011% of alleles in individuals of African descent in gnomAD. In summary, this variant is likely pathogenic for autosomal recessive TTN-related disorders. However, it is uncertain if this variant would be causative for autosomal dominant TTN-related disorders.