rs72646831
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.57331C>T(p.Arg19111*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,050 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: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
TTN
NM_001267550.2 stop_gained
NM_001267550.2 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.76
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 2-178597751-G-A is Pathogenic according to our data. Variant chr2-178597751-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 47121.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178597751-G-A is described in Lovd as [Pathogenic]. Variant chr2-178597751-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.57331C>T | p.Arg19111* | stop_gained | 294/363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.57331C>T | p.Arg19111* | stop_gained | 294/363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461050Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726804
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2024 | 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; Located in the A-band region of TTN in which the majority of loss of function variants have been associated with autosomal dominant titinopathies (PMID: 22335739); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 38438525, 37221934, 24119082, 28416588, 31514951, 33874732, 32778822, 31737537, 26735901, 36264615, 36396199) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Nov 08, 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 | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Arg19111*) 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: 22335739, 31514951). ClinVar contains an entry for this variant (Variation ID: 47121). 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. - |
Primary dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 17, 2013 | The Arg16543X variant in TTN has not been reported in the literature but has bee n identified by our laboratory in one Egyptian individual with DCM (LMM unpublis hed data). The variant is listed in dbSNP with a frequency of 1/376 chromosomes (this data represents a clinical cohort) and was absent from European American and African American chromosomes by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs72646831). This nonsense variant leads to a pr emature termination codon at position 16543, which is predicted to lead to a tru ncated or absent protein. Truncating variants in TTN are strongly associated wit h DCM (Herman 2012). In summary, the Arg16543X variant is likely to be pathogeni c, but additional information is needed to fully assess its clinical significanc e. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 02, 2024 | The c.30136C>T (p.R10046*) alteration, located in exon 122 (coding exon 121) of the TTN gene, consists of a C to T substitution at nucleotide position 30136. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 10046. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This exon is located in the A-band of the N2-B isoform of the titin protein and is constitutively expressed in TTN transcripts (percent spliced in or PSI 100%). The TTN c.30136C>T alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This variant has been reported in overlapping dilated cardiomyopathy (DCM) cohorts, where co-segregation with DCM was demonstrated in one family (Herman, 2012; Merlo, 2013; Dal Ferro, 2017). Based on the available evidence, this alteration is classified as pathogenic. - |
not specified Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 22, 2015 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p.Arg17470Stop (R17470X; c.52408 C>T) in the TTN gene This variant produces a premature stop codon in exon 244 of the TTN gene, and is expected to result in production of an abnormal, prematurely truncated protein or an absence of protein product due to nonsense mediated mRNA decay. The Arg17470Stop variant has been reported to segregate with disease in 3 individuals in one family diagnosed with DCM (a father and his two children) at ages 35, 48, and 40 (Herman et al. 2012). This is the only case data available. Truncating TTN variants have been shown by Herman et al. (2012) to be present in 27% of patients with familial dilated cardiomyopathy (DCM) versus approximately 1% of patients with hypertrophic cardiomyopathy (HCM) and 3% of controls. Herman et al. observed strong cosegregation (lod score, 9.3) of nonsense and frameshift variants with clinical status among 60 members of 16 families affected by DCM, indicating an odds of approximately 1 in 10^9 that the segregation of these TTN variants occurred by chance. However, the presence of truncating TTN variants in controls indicates that not all such variants can be presumed to be pathogenic. Another word of caution: Norton et al. (2013, Ray Hershberger’s group) found that not all TTN truncating variants segregate with disease. Herman et al. reported that TTN truncating mutations found in subjects with dilated cardiomyopathy (versus those found in subjects without the disease) were nonrandomly distributed within titin: they were overrepresented in the A-band region. Our patient’s variant is also located in the A-band region, according to the GeneDx report. In total the variant has not been seen in ~6000 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4000 Caucasian and ~2000 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Mexican. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. It is not present in 1000 Genomes (as of March 26, 2014). It is listed in dbSNP as rs72646831, and appears to have been submitted by Robert Livingston’s lab at the University of Washington. - |
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
Pathogenic
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at