Submissions for variant NM_001267550.2(TTN):c.107635C>T (p.Gln35879Ter)

gnomAD frequency: 0.00001  dbSNP: rs757082154

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000735131	SCV000237023	pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	Reported in a patient with muscle weakness and reduced ejection fraction who also harbored an additional TTN loss of function variant, but phase was not reported (Savarese et al., 2018); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 113 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Located in the M-line region of the titin protein, where the majority of pathogenic truncating variants associated with autosomal recessive muscular dystrophy have been reported (Carmignac et al., 2007); This variant is associated with the following publications: (PMID: 32039858, 17444505, 32528171, 27796757, 29435569, 34935411, 28295036, 32778822, 34106991, 23975875)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415078	SCV000492942	uncertain significance	Limb-girdle muscle weakness; Limb-girdle muscle atrophy	2014-10-09	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414825	SCV000492944	likely pathogenic	Limb-girdle muscular dystrophy; Muscular dystrophy; Waddling gait; Proximal lower limb amyotrophy; Decreased patellar reflex	2015-02-04	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV004528965	SCV000845473	pathogenic	TTN-related disorder	2018-08-07	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000714746	SCV000845474	pathogenic	Lower limb muscle weakness	2018-08-07	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000735131	SCV000863331	pathogenic	not provided	2018-09-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000735131	SCV001246029	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	TTN: PVS1, PM2, PM3, PS4:Supporting
Invitae	RCV001383196	SCV001582272	pathogenic	Dilated cardiomyopathy 1G; Autosomal recessive limb-girdle muscular dystrophy type 2J	2023-04-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 202529). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive TTN-related myopathy (PMID: 27796757, 28295036, 29435569). This variant is present in population databases (rs757082154, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln35879*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein.
3billion	RCV001808462	SCV002058628	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2J	2022-01-03	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000202529, PMID:28295036). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002516949	SCV003761418	pathogenic	TTN-related myopathy	2023-01-25	criteria provided, single submitter	curation	The heterozygous p.Gln35879Ter variant in TTN was identified by our study, in the compound heterozygous state with a likely pathogenic variant (NC_000002.12:g.178543072del), in one individual with limb-girdle muscular dystrophy. This individual also carried a likely pathogenic variant (NC_000002.12:g.178543072del), however the phase of these variants are unknown at this time. The p.Gln35879Ter variant in TTN has been previously reported in 16 unrelated individuals with TTN-related myopathy (PMID: 34106991, PMID: 29435569, PMID: 28295036) and segregated with disease in 2 affected relatives in one family (PMID: 34106991), but has been identified in 0.003% (1/34510) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs757082154). 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. Of these 16 affected individuals (PMID: 34106991, PMID: 29435569, PMID: 28295036), 3 were homozygotes (PMID: 28295036) and 6 were compound heterozygotes who carried pathogenic or likely pathogenic variants in trans (PMID: 34106991, ClinVar Variation ID: 374145; PMID: 28295036, ClinVar Variation ID: 374145), which increases the likelihood that the p.Gln35879Ter variant is pathogenic. This variant has also been reported in ClinVar (Variation ID: 202529) and has conflicting interpretations of pathogenicity. This nonsense variant leads to a premature termination codon at position 35879. This alteration occurs within the terminal 50 bases of the second to last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. Loss of function of the TTN gene is an established disease mechanism in autosomal recessive limb-girdle muscular dystrophy 10. In summary, this variant meets criteria to be classified as pathogenic for limb-girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3_VeryStrong (Richards 2015).
Revvity Omics, Revvity	RCV000735131	SCV003823757	pathogenic	not provided	2022-08-17	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003228796	SCV003925567	pathogenic	Early-onset myopathy with fatal cardiomyopathy		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017470	SCV004847620	pathogenic	Neuromuscular disease	2019-04-12	criteria provided, single submitter	clinical testing	The p.Gln33311X variant in TTN, reported in the literature as p.Gln35879X (NM_001267550.1), has been identified in the compound heterozygous or homozygous state in greater than 15 individuals with distal myopathy (Eliva 2017, Peric 2017, Savarese 2018). The majority of these individuals were Serbian, suggesting that this variant is likely a founder mutation in that population (Peric 2017). It has also been identified in 3/248904 chromosomes by gnomAD (http://gnomad.broadinstitute.org) and has been reported in ClinVar (Variation ID # 202529). This nonsense variant leads to a premature termination codon at position 33311. This alteration occurs within the terminal 50 bases of the second to last exon and is therefore likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive distal myopathy. ACMG/AMP criteria applied: PM3_VeryStrong, PM2, PP1.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414850	SCV000492678	likely pathogenic	Myopathy; Rimmed vacuoles; Lower limb muscle weakness	2016-01-04	no assertion criteria provided	clinical testing