Submissions for variant NM_001267550.2(TTN):c.39974-11T>G

gnomAD frequency: 0.00006  dbSNP: rs758597536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV001268728	SCV001447870	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
GeneDx	RCV001268728	SCV001767621	pathogenic	not provided	2022-03-07	criteria provided, single submitter	clinical testing	Published mRNA functional studies demonstrate this variant results in two abnormally spliced transcripts (Bryen et al., 2019); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 31660661, 33977140)
CeGaT Center for Human Genetics Tuebingen	RCV001268728	SCV001962330	pathogenic	not provided	2021-09-01	criteria provided, single submitter	clinical testing
Invitae	RCV001880170	SCV002208293	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-10-15	criteria provided, single submitter	clinical testing	This sequence change falls in intron 212 of the TTN gene. It does not directly change the encoded amino acid sequence of the TTN protein. This variant is present in population databases (rs758597536, gnomAD 0.02%). This variant has been observed in individuals with autosomal recessive arthrogryposis multiplex congenita and myopathy (PMID: 31660661). ClinVar contains an entry for this variant (Variation ID: 987382). Studies have shown that this variant is associated with altered splicing, resulting in a premature frameshift or an in-frame loss of exon 213 (also known as exon 214) (PMID: 31660661). 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). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002491873	SCV002798870	likely pathogenic	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	2021-10-26	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225966	SCV003922359	pathogenic	TTN-related myopathy	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.39974-11T>G variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (ClinVar Variation ID: 577790), in one individual with congenital myopathy. Trio exome analysis revealed that this variant was in trans with a likely pathogenic variant (ClinVar Variation ID: 577790). The c.39974-11T>G variant in TTN has been previously reported in eight unrelated individuals with titin-related myopathy (PMID: 31660661) but has been identified in 0.01% (4/41260) of non-Finnish European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs758597536). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID:987382) and has been interpreted as pathogenic by Invitae, GeneDx, Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, and the CeGaT Center for Human Genetics Tuebingen. The eight unrelated affected individuals previously reported were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans (PMID: 31660661), which increases the likelihood that the c.39974-11T>G variant is pathogenic. RT-PCR and RNAseq analysis performed on skeletal muscle tissue from affected individuals shows altered splicing resulting in either use of a cryptic 3′ splice site that abnormally includes 10 nucleotides of intron 213, leading to a frameshift and premature termination or in-frame exon skipping of exon 214 leading to an in-frame deletion of 28 amino acids in one of the proline-glutamine-valine-lysine (PEVK) regions of the gene (PMID: 31660661). This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive titin-related myopathy. ACMG/AMP Criteria applied: PM3_VeryStrong, PS3_Moderate, PM2_Supporting (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004538548	SCV004118993	pathogenic	TTN-related disorder	2023-02-15	criteria provided, single submitter	clinical testing	The TTN c.39974-11T>G variant is predicted to interfere with splicing. This variant has been reported in the compound heterozygous state with a second pathogenic TTN variant in eleven individuals from ten families with autosomal recessive arthrogryposis multiplex congenita and myopathy (Table S1, Bryen SJ et al. 2020. PubMed ID: 31660661; Suppl. Table 2, Ravenscroft G et al. 2020. PubMed ID: 33060286). Functional studies show this variant causes abnormal splicing, resulting in a frameshift, or an in-frame deletion of 28 amino-acids caused by a skip of exon 214 (Bryen SJ et al. 2020. PubMed ID: 31660661). This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179514069-A-C). Taken together, in the context of autosomal recessive TTN-related disorders, this variant is interpreted as pathogenic. However, RNAseq studies from heart tissue indicate this exon is not commonly included in TTN mRNA transcripts (PSI < 15%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). Of note, variants found in exons not spliced into titin isoforms expressed in the heart (non-cardiac exons with ‘Percent Spliced In’ (PSI) < 15%) are unlikely to be associated with dilated cardiomyopathy (DCM) (Schafer S et al. 2017. PubMed ID: 27869827). Therefore, in the context of autosomal dominant TTN-related disorders, this variant is interpreted as a variant of uncertain significance.