rs878854299
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.35794G>T(p.Glu11932*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,596,686 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). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.35794G>T | p.Glu11932* | stop_gained | 162/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.35794G>T | p.Glu11932* | stop_gained | 162/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152040Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000916 AC: 2AN: 218240Hom.: 0 AF XY: 0.00000839 AC XY: 1AN XY: 119136
GnomAD4 exome AF: 0.0000187 AC: 27AN: 1444646Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 11AN XY: 716992
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152040Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74264
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 15, 2021 | Observed with a splice variant on the opposite allele (in trans) in a patient with a congenital TTN-related disorder in published literature (Oates et al., 2018); Nonsense variant predicted to result in protein truncation or nonsense mediated decay; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 32778822, 29691892) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2018 | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 01, 2022 | - - |
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 | Nov 30, 2023 | This sequence change creates a premature translational stop signal (p.Glu11932*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive centronuclear myopathy (PMID: 29691892). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 238750). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). 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). For these reasons, this variant has been classified as Pathogenic. - |
Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 09, 2025 | The heterozygous p.Glu11932Ter variant in TTN was identified by our study in one individual with early onset myopathy, in the compound heterozygous state along with another pathogenic variant. The phase of these variants is unknown at this time. The p.Glu11932Ter variant has been reported in 6 families with TTN-related myopathy (PMID: 29691892), and has been identified in 0.003% (30/1171268) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs878854299). 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 the 7 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the p.Glu11932Ter variant is pathogenic (Variation ID: 1067510, 2938083, 404786, 223329; PMID: 29691892). This variant has also been reported in ClinVar (Variation ID: 238750) and has been interpreted as pathogenic/likely pathogenic by Labcorp, GeneDx, MGZ Medical Genetics Center, and CeGaT Center for Human Genetics Tuebingen, and as a variant of uncertain significance by Eurofins Ntd Llc. This nonsense variant leads to a premature termination codon at position 11932 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 TTN-related myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TTN-related myopathy. ACMG/AMP Criteria applied: PM3_very-strong, PVS1, PM2_supporting (Richards 2015). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at