Submissions for variant NM_001267550.2(TTN):c.35890C>T (p.Arg11964Ter)

gnomAD frequency: 0.00006  dbSNP: rs1266298136

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000685825	SCV000813324	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2019-06-05	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the TTN gene (p.Arg11964*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with TTN-related disease. 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.
AiLife Diagnostics, AiLife Diagnostics	RCV002223904	SCV002503067	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV002223904	SCV002578830	uncertain significance	not provided	2023-06-14	criteria provided, single submitter	clinical testing	Reported in an individual with early onset atrial fibrillation in published literature (Choi et al., 2018); 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 in which the majority of pathogenic variants have been reported in association with autosomal recessive titinopathies (Fernandez-Marmiesse et al., 2017; Chervinsky et al., 2018; Bryen, et al., 2020; Savarese et al., 2020); This variant is associated with the following publications: (PMID: 30535219)
Fulgent Genetics, Fulgent Genetics	RCV002493142	SCV002779925	uncertain significance	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J; Tibial muscular dystrophy; Myopathy, myofibrillar, 9, with early respiratory failure; Early-onset myopathy with fatal cardiomyopathy; Hypertrophic cardiomyopathy 9	2021-07-02	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535706	SCV004119258	likely pathogenic	TTN-related disorder	2023-06-27	criteria provided, single submitter	clinical testing	The TTN c.35890C>T variant is predicted to result in premature protein termination (p.Arg11964*). This variant has been reported in an individual with early onset atrial fibrillation (Choi et al., 2018. PubMed ID: 30535219). This variant is reported in 0.081% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179530504-G-A). This variant is found in an exon specific to the TTN metatranscript and is not included in the skeletal muscle isoform (NM_133378.4); however, many other protein truncating variants in these 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). In summary, we categorize the c.37862dup as likely pathogenic for autosomal recessive TTN-related myopathy. It is uncertain if this variant would be disease causing for dominant TTN-related disorders.