rs1553742630
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1PM2PP5
The NM_001267550.2(TTN):c.42598_42599insG(p.Met14200SerfsTer8) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 frameshift
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | c.42598_42599insG | p.Met14200SerfsTer8 | frameshift_variant | Exon 231 of 363 | ENST00000589042.5 | NP_001254479.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | c.42598_42599insG | p.Met14200SerfsTer8 | frameshift_variant | Exon 231 of 363 | 5 | NM_001267550.2 | ENSP00000467141.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 33
GnomAD4 genome
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
This sequence change creates a premature translational stop signal (p.Met14200Serfs*8) 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: 452205). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, internal data). 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. -
Primary dilated cardiomyopathy Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Centronuclear myopathy Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Cardiovascular phenotype Pathogenic:1
The c.15403_15404insG variant, located in coding exon 58 of the TTN gene, results from an insertion of one nucleotide at position 15403, causing a translational frameshift with a predicted alternate stop codon (p.M5135Sfs*8). This exon is located in the I-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 has been reported, reported as c.34894_34895insG, in a male infant (Ceyhan-Birsoy O et al. Am J Hum Genet, 2019 01;104:76-93). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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). As such, this alteration is classified as likely pathogenic. -
not provided Uncertain:1
A variant of uncertain significance has been identified in the TTN gene. The c.37675_37676insG variant in the TTN gene has not been reported as a pathogenic or benign variant to our knowledge. This variant causes a shift in reading frame starting at codon methionine 12559, changing it to an serine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Met12559SerfsX8. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. The c.37675_37676insG variant has not been observed in a large population cohort (Exome Variant Server). Other frameshift variants in the TTN gene have been reported in Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014). Nevertheless, the majority of pathogenic variants reported in association with autosomal dominant dilated cardiomyopathy (DCM) are truncating variants in the A-band region of titin, while the clinical significance of variants in the I-band, where c.37675_37676insG occurs, is not well characterized. Furthermore, truncating TTN variants have been reported in approximately 3% of control alleles (Herman et al., 2012). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at