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rs727503688

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_001267550.2(TTN):​c.7642C>T​(p.Gln2548Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. 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

Genomes: not found (cov: 32)

Consequence

TTN
NM_001267550.2 stop_gained

Scores

5
1
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 6.68
Variant links:
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]
TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 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 2-178773322-G-A is Pathogenic according to our data. Variant chr2-178773322-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166307.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TTNNM_001267550.2 linkuse as main transcriptc.7642C>T p.Gln2548Ter stop_gained 33/363 ENST00000589042.5
TTNNM_133379.5 linkuse as main transcriptc.7642C>T p.Gln2548Ter stop_gained 33/46 ENST00000360870.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TTNENST00000589042.5 linkuse as main transcriptc.7642C>T p.Gln2548Ter stop_gained 33/3635 NM_001267550.2 P1
TTNENST00000360870.10 linkuse as main transcriptc.7642C>T p.Gln2548Ter stop_gained 33/465 NM_133379.5 Q8WZ42-6
TTN-AS1ENST00000659121.1 linkuse as main transcriptn.1640G>A non_coding_transcript_exon_variant 11/13

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

TTN-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 16, 2024The TTN c.7642C>T variant is predicted to result in premature protein termination (p.Gln2548*). This variant occurs within the I-band region of the titin protein. RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%, Roberts AM et al. 2015. PubMed ID: 25589632; https://cardiodb.org/titin/titin_transcripts.php). TTN truncating variants are reported in 1-2% of presumably healthy individuals, but occur more frequently in exons with low PSI values (Roberts AM et al. 2015. PubMed ID: 25589632; Herman DS et al. 2012. PubMed ID: 22335739). To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. Of note, truncating TTN variants in constitutive exons (PSI > 90%) are significantly associated with dilated cardiomyopathy (DCM) irrespective of their position in TTN (Schafer S et al. 2017. PubMed ID: 27869827). In addition, truncating TTN variants have also been associated with autosomal recessive congenital myopathy (Ceyhan-Birsoy O et al. 2013. PubMed ID: 23975875). Therefore, the c.7642C>T (p.Gln2548*) variant is interpreted as likely pathogenic for recessive and dominant TTN-related disorders. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 10, 2014Variant classified as Uncertain Significance - Favor Pathogenic. The p.Gln2548X variant in TTN gene has not been previously reported in individuals with cardiom yopathy or in large population studies. This nonsense variant leads to a prematu re termination codon at position 2548, which is predicted to lead to a truncated or absent protein. However, variants in the I-band of the TTN gene, where this variant is located, occur at a greater frequency in controls than in individuals with DCM (Pugh 2014). This decreases the likelihood, but does not eliminate the possibility that this variant has a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Gln254 8X variant is uncertain. -
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJun 20, 2022In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, truncating variants in this region have also been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875). ClinVar contains an entry for this variant (Variation ID: 166307). This variant has not been reported in the literature in individuals affected with TTN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln2548*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
38
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A;A;A;A;A;A;A
Vest4
0.95
GERP RS
5.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs727503688; hg19: chr2-179638049; API