2-178786081-G-A
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_001267550.2(TTN):c.2137C>T(p.Arg713Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,766 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R713R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.2137C>T | p.Arg713Ter | stop_gained | 14/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.2137C>T | p.Arg713Ter | stop_gained | 14/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.2137C>T | p.Arg713Ter | stop_gained | 14/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.2137C>T | p.Arg713Ter | stop_gained | 14/46 | 5 | NM_133379.5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461766Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727186
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 08, 2019 | This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 26, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The Arg713X var iant in TTN has not been previously reported in individuals with cardiomyopathy and was absent from large population studies. This nonsense variant leads to a p remature termination codon at position 713, which is predicted to lead to a trun cated or absent protein. Nonsense and other truncating variants in TTN are stron gly associated with DCM; however, the majority of such variants are located in t he exons encoding for the A-band region of the protein (Herman 2012, Pugh 2014), while this variant occurs in the Z-disc. In summary, while there is some suspic ion for a pathogenic role, the clinical significance of the Arg713X variant is u ncertain. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 05, 2022 | In 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 Z band of TTN (PMID: 25589632). Variants in this region may be clinically relevant, but have not been definitively shown to cause cardiomyopathy or neuromuscular disease (PMID: 27493940, 32778822). ClinVar contains an entry for this variant (Variation ID: 180003). This premature translational stop signal has been observed in individual(s) with clinical features of TTN-related conditions (PMID: 25163546, 30365001). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg713*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. - |
Dilated cardiomyopathy 1G Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2023 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 22, 2020 | The p.R667* variant (also known as c.1999C>T), located in coding exon 12 of the TTN gene, results from a C to T substitution at nucleotide position 1999. This changes the amino acid from an arginine to a stop codon within coding exon 12. This exon is located in the Z-disk 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 was detected in a dilated cardiomyopathy cohort; however, details were limited (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Truncating variants in the A-band of titin are the most common cause of dilated cardiomyopathy (DCM), and, regardless of their position, truncating variants encoded in constitutive exons (PSI >90%) have been found to be significantly associated with 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; Schafer S et al. Nat. Genet., 2017 01;49:46-53). However, TTN truncating variants have also been reported in 1-3% of the general population (Herman DS et al. N. Engl. J. Med. 2012;366:619-28). Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at