rs727504535
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Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001267550.2(TTN):c.98994del(p.Lys32998AsnfsTer63) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,450,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
TTN
NM_001267550.2 frameshift
NM_001267550.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.36
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 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 2-178538834-GT-G is Pathogenic according to our data. Variant chr2-178538834-GT-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178913.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=3, Uncertain_significance=1}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.98994del | p.Lys32998AsnfsTer63 | frameshift_variant | 354/363 | ENST00000589042.5 | NP_001254479.2 | |
| TTN-AS1 | NR_038272.1 | n.787del | non_coding_transcript_exon_variant | 5/17 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.98994del | p.Lys32998AsnfsTer63 | frameshift_variant | 354/363 | 5 | NM_001267550.2 | ENSP00000467141 | P1 | |
| TTN-AS1 | ENST00000659121.1 | n.416+15201del | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000415 AC: 1AN: 240770Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130408
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GnomAD4 exome AF: 0.00000276 AC: 4AN: 1450270Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2AN XY: 720218
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:8Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 13, 2023 | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). This variant is predicted to result in premature termination and the loss of a functional protein in three main isoforms (major cardiac long isoform: NM_001256850.1, major skeletal muscle long isoform: NM_133378.4, and the inferred complete isoform: NM_001267550.1). This variant is in the TTN A-band. Premature termination variants that occur in this region are enriched in cardiomyopathy patients compared to the general population (PMID: 31849696), while their significance for muscular dystrophy is uncertain. Premature termination variants in the TTN gene have also been found in healthy individuals (PMID: 25589632). - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Frameshift 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 (Herman et al., 2012); This variant is associated with the following publications: (PMID: 33500567, 22335739, 35605965) - |
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Undiagnosed Diseases Network, NIH | Jun 05, 2024 | - - |
TTN-related disorder Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 10, 2024 | The TTN c.98994delA variant is predicted to result in a frameshift and premature protein termination (p.Lys32998Asnfs*63). This variant was reported in the compound heterozygous state in two siblings with autosomal recessive TTN-related myopathy, and a maternal family history of cardiomyopathy (Family C in Averdunk et al. 2022. PubMed ID: 35605965). This variant was also reported in a large cohort study of individuals with left ventricular noncompaction (Supp. Table S2 Mazzarotto et al. 2021. PubMed ID: 33500567). This variant occurs within the A-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). In addition, many cases of recessive TTN-related myopathies in which the individual is compound heterozygous for two loss of function variants in TTN have also been reported (See Ceyhan-Birsoy O. et al. 2013. PMID: 23975875; Chauveau C et al. 2014. PMID: 24105469; Evilä A et al. 2016. PMID: 27796757; Ge et al. 2019. PubMed ID: 31053406). This variant is reported in 0.00091% of alleles in individuals of European (non-Finnish) descent in gnomAD. The c.98994delA variant is interpreted as likely pathogenic for autosomal dominant and recessive TTN-related disorders. - |
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 04, 2024 | This sequence change creates a premature translational stop signal (p.Lys32998Asnfs*63) 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 individual(s) with clinical features of autosomal dominant TTN-related conditions and/or clinical features of autosomal recessive congenital myopathy (PMID: 33500567, 35605965). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 178913). 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. - |
Autosomal recessive titinopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 10, 2024 | The heterozygous p.Lys32998AsnfsTer63 variant in TTN was identified by our study in 2 affected siblings with congenital myopathy, in the compound heterozygous state along with a likely pathogenic variant (PMID: 35605965). Trio exome analysis revealed that this variant was in trans with the likely pathogenic variant. The p.Lys32998AsnfsTer63 variant has not been previously reported in the literature in individuals with congenital myopathy, but has been identified in 0.0003% (4/1174272) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs727504535). 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: 178913) and has been interpreted as pathogenic/likely pathogenic by many submitters and a variant of uncertain significance by Athena Diagnostics. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 32998 and leads to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TTN gene is an established disease mechanism in congenital myopathy. In summary, this variant meets criteria to be classified as pathogenic for congenital myopathy. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015). - |
Primary familial dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2021 | Variant summary: TTN c.91290delA (p.Lys30430AsnfsX63) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant occurs in the A-band region of titin within a constitutively expressed exon. The variant allele was found at a frequency of 4.2e-06 in 240770 control chromosomes (gnomAD). To our knowledge, no occurrence of c.91290delA in individuals affected with Dilated Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters have assessed this variant since 2014: two have classified it as likely pathogenic, and one as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Primary dilated cardiomyopathy Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 18, 2019 | The p.Lys30430AsnfsX63 variant in TTN has been identified in 1 individual with DCM (LMM data) and was idnetified in 1/109666 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 30430 and lead to a premature termination codon 63 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Frameshift and other truncating variants in TTN are 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.Lys30430AsnfsX63 variant is located in A-band in a highly expressed exon. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant DCM. ACMG/AMP Criteria applied: PVS1, PM2. - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 08, 2021 | The c.71799delA pathogenic mutation, located in coding exon 181 of the TTN gene, results from a deletion of one nucleotide at nucleotide position 71799, causing a translational frameshift with a predicted alternate stop codon (p.K23933Nfs*63). This variant has been detected in individuals with dilated cardiomyopathy (Ambry internal data). 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 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 alteration is interpreted as a disease-causing mutation. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at