rs974671846

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001267550.2(TTN):​c.59693G>A​(p.Trp19898*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,004 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: 32)

Consequence

TTN
NM_001267550.2 stop_gained

Scores

5
2

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.86

Publications

1 publications found
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 2-178592211-C-T is Pathogenic according to our data. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-178592211-C-T is described in CliVar as Likely_pathogenic. Clinvar id is 504986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TTNNM_001267550.2 linkc.59693G>A p.Trp19898* stop_gained Exon 302 of 363 ENST00000589042.5 NP_001254479.2 A0A0A0MTS7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TTNENST00000589042.5 linkc.59693G>A p.Trp19898* stop_gained Exon 302 of 363 5 NM_001267550.2 ENSP00000467141.1 A0A0A0MTS7

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152004
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00110
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
35
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152004
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74238
show subpopulations
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
41408
American (AMR)
AF:
0.00
AC:
0
AN:
15264
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5156
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10606
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67972
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Sep 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Trp19898*) 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 variant has not been reported in the literature in individuals affected with TTN-related conditions. ClinVar contains an entry for this variant (Variation ID: 504986). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hypertrophic cardiomyopathy 9 Pathogenic:1
-
Neuberg Centre For Genomic Medicine, NCGM
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The stop gained c.59693G>A (p.Trp19898Ter) variant in TTN gene has been submitted in ClinVar as Likely pathogenic variant but not reported in affected individuals. The variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

not provided Pathogenic:1
Jun 16, 2025
GeneDx
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Reported in an individual with propionic acidemia and cardiomyopathy with worsening heart failure despite appropriate metabolic management for propionic acidemia (PMID: 36393899); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 36393899, 22335739, 32778822) -

Primary dilated cardiomyopathy Pathogenic:1
Apr 27, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.Trp17330X variant in TTN has not been previously reported in individuals w ith cardiomyopathy or in large population studies. This nonsense variant leads t o a premature termination codon at position 17330, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN ar e strongly associated with DCM if they impact the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expressed in the heart (Roberts 2015). The p.Trp17330X variant is located in A-band in the highly expressed exon 251. In summary, although additional studies are required to fully establish its clinical significance, the p.Trp17330X variant is likely pathogenic. -

Cardiovascular phenotype Pathogenic:1
Apr 13, 2025
Ambry Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.W10833* variant (also known as c.32498G>A), located in coding exon 129 of the TTN gene, results from a G to A substitution at nucleotide position 32498. This changes the amino acid from a tryptophan to a stop codon within coding exon 129. 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 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 (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; Akhtar MM et al. Circ Heart Fail, 2020 Oct;13:e006832; Massier M et al. Clin Genet, 2025 Jan). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Pathogenic
0.66
CADD
Pathogenic
61
DANN
Benign
0.97
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.1
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
7.9
Vest4
0.95
GERP RS
6.0
Mutation Taster
=0/200
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs974671846; hg19: chr2-179456938; API