rs757082154
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_StrongPP5
The NM_001267550.2(TTN):c.107635C>T(p.Gln35879*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000753 in 1,461,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
TTN
NM_001267550.2 stop_gained
NM_001267550.2 stop_gained
Scores
5
2
Clinical Significance
Conservation
PhyloP100: 6.56
Genes affected
TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
PP5
Variant 2-178527491-G-A is Pathogenic according to our data. Variant chr2-178527491-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 202529.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=12, Likely_pathogenic=1}. Variant chr2-178527491-G-A is described in Lovd as [Pathogenic]. Variant chr2-178527491-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.107635C>T | p.Gln35879* | stop_gained | 362/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.107635C>T | p.Gln35879* | stop_gained | 362/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248904Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135050
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GnomAD4 exome AF: 0.00000753 AC: 11AN: 1461646Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727098
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:14Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 18, 2022 | 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) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 11, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | TTN: PVS1, PM2, PM3, PS4:Supporting - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | 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. - |
Neuromuscular disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 12, 2019 | 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. - |
TTN-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 05, 2023 | 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. - |
Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C2673677:Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Oct 15, 2024 | ACMG Criteria: PP5, PM2_P, PM3, PVS1; Variant was found in heterozygous state - |
Muscular dystrophy;C0231712:Waddling gait;C0686353:Limb-girdle muscular dystrophy;C1836767:Proximal lower limb amyotrophy;C3277184:Decreased patellar reflex Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 04, 2015 | - - |
Lower limb muscle weakness Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
Myopathy;C1836296:Lower limb muscle weakness;C1853932:Rimmed vacuoles Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 04, 2016 | - - |
TTN-related myopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 25, 2023 | 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). - |
Limb-girdle muscle atrophy;C1858127:Limb-girdle muscle weakness Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Oct 09, 2014 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at