rs878854324
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.61921C>T(p.Arg20641Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000124 in 1,613,380 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
TTN
NM_001267550.2 stop_gained
NM_001267550.2 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.50
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-178589804-G-A is Pathogenic according to our data. Variant chr2-178589804-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 238819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178589804-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.61921C>T | p.Arg20641Ter | stop_gained | 304/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.3189-1335G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.61921C>T | p.Arg20641Ter | stop_gained | 304/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-7792G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461308Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0AN XY: 726938
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | The heterozygous p.Arg20641Ter variant in TTN was identified by our study, in the compound heterozygous state with a variant of uncertain significance (ClinVar Variation ID: 1304094), in one individual with limb girdle muscular dystrophy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (ClinVar Variation ID: 1304094). The p.Arg20641Ter variant in TTN has not been previously reported in individuals with limb girdle muscular dystrophy 10 but has been identified in 0.002% (1/41434) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs878854324). 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: 238819) and has been interpreted as pathogenic by GeneDx and as likely pathogenic by Ambry and Invitae. This nonsense variant leads to a premature termination codon at position 20641, 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 limb girdle muscular dystrophy 10. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for limb girdle muscular dystrophy 10. ACMG/AMP Criteria applied: PVS1, PM2_Supporting (Richards 2015). - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change creates a premature translational stop signal (p.Arg20641*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 29540472, 34315225; Invitae). ClinVar contains an entry for this variant (Variation ID: 238819). This variant is located in the A band of TTN (PMID: 25589632). Truncating variants in this region are significantly overrepresented in patients affected with dilated cardiomyopathy (PMID: 25589632). 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2022 | Reported in a patient with dilated cardiomyopathy, however, additional detailed clinical information and segregation analysis were not provided (Haebroek et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); Located in the A-band region of the TTN gene, where the majority of truncating pathogenic variants associated with dilated cardiomyopathy have been reported (Herman et al., 2012); 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: 25589632, 11717165, 23518707, 23418287, 1745277, 24395473, 22335739, 12145747, 18948003, 21810661, 17444505, 24105469, 32880476, 34315225, 29540472) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2024 | The p.R11576* pathogenic mutation (also known as c.34726C>T), located in coding exon 131 of the TTN gene, results from a C to T substitution at nucleotide position 34726. This changes the amino acid from an arginine to a stop codon within coding exon 131. This exon is located in the A-band region of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This variant (also referred to as p.R20641*, c.61921C>T) has been detected in individuals from dilated cardiomyopathy cohorts (Enriquez A et al. Circ Arrhythm Electrophysiol, 2021 Sep;14:e010006; Zhao Y et al. Signal Transduct Target Ther, 2023 Jun;8:226). 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 A-band are the most common cause of dilated cardiomyopathy (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). TTN truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with DCM regardless of their position in titin (Schafer S et al. Nat. Genet., 2017 01;49:46-53). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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