Submissions for variant NM_001267550.2(TTN):c.107578C>T (p.Gln35860Ter)

gnomAD frequency: 0.00001  dbSNP: rs1009131948

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619039	SCV000735349	likely pathogenic	Cardiovascular phenotype	2021-12-01	criteria provided, single submitter	clinical testing	The p.Q26795* variant (also known as c.80383C>T), located in coding exon 189 of the TTN gene, results from a C to T substitution at nucleotide position 80383. This changes the amino acid from a glutamine to a stop codon within coding exon 189. This exon is located in the M-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 99%). This alteration (reported as NM_001267550.2 c.107578C>T p.Q35860*) has been identified in two individuals in an early onset atrial fibrillation cohort (Choi SH et al. JAMA, 2018 12;320:2354-2364). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. While truncating variants in TTN are present in 1-3% of the general population, truncating variants in the M-band have been reported in association with autosomal recessive titinopathies, primarily presenting with skeletal myopathy phenotypes (Ceyhan-Birsoy O et al. Neurology. 2013 Oct 1;81(14):1205-14; De Cid R et al. Neurology. 2015;85(24):2126-35). In addition, regardless of their position, TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with dilated cardiomyopathy (DCM), though truncating variants in the A-band are the most common cause of DCM (Herman DS et al. N. Engl. J. Med., 2012 Feb;366:619-28; Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the majority of available evidence to date, this variant is likely to be pathogenic in association with autosomal recessive titinopathy; however, the clinical significance of this alteration with respect to cardiomyopathy remains unclear.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001004985	SCV001164535	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2018-12-03	criteria provided, single submitter	research	The heterozygous p.Gln35860Ter variant in TTN was identified by our study in one individual in the compound heterozygous state, with another pathogenic variant, in one individual with limb-girdle muscular dystrophy (LGMD). The presence of this variant in combination with a pathogenic variant and in an individual with limb-girdle muscular dystrophy (LGMD) increases the likelihood that the p.Gln35860Ter variant is pathogenic. This variant has been identified in 0.001083% (3/276994) of chromosomes in the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 35860, which is predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive LGMD. In summary, this variant meets criteria to be classified as pathogenic for LGMD in an autosomal recessive manner based on the predicted impact of the variant and the presence of a pathogenic variant in an individual with limb-girdle muscular dystrophy (LGMD). ACMG/AMP Criteria applied: PM2, PVS1, PM3 (Richards 2015).
Invitae	RCV001389433	SCV001590801	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln35860*) 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 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy or early-onset atrial fibrillation (PMID: 30535219, 31407473, 31737537; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with dilated cardiomyopathy (Invitae); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 518510). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, Invitae internal data). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002483701	SCV002785156	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	2021-09-15	criteria provided, single submitter	clinical testing
GeneDx	RCV003151795	SCV003840876	pathogenic	not provided	2023-03-10	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Located in the M-line region of TTN in which the majority of loss of function variants have been associated with autosomal recessive titinopathies (Carmignac et al., 2007); 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; This variant is associated with the following publications: (PMID: 22335739, 24503780, 31737537, 34135346, 17444505, 34495297, 30535219, 31407473)