rs571702144
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.53206C>T(p.Arg17736Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000031 in 1,613,010 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R17736R) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.53206C>T | p.Arg17736Ter | stop_gained | 277/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.53206C>T | p.Arg17736Ter | stop_gained | 277/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+9801G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461114Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726866
GnomAD4 genome AF: 0.00000658 AC: 1AN: 151896Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74162
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 20, 2023 | This sequence change creates a premature translational stop signal (p.Arg17736*) 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 present in population databases (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with atrial fibrillation, dilated cardiomyopathy, and/or sudden infant death syndrome (PMID: 25163546, 28045975, 29544605, 30535219, 31983221, 34495297, 35653365). This variant is also known as c.C26587T (p.R8863X) and c.26011C>T (p.Arg8671*). ClinVar contains an entry for this variant (Variation ID: 1066067). 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. - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 2022 | Reported in association with DCM, early-onset atrial fibrillation, SIDS, and skeletal muscle disease in published literature (Haas et al., 2015; Franaszczyk et al., 2017; Choi et al., 2018; Tester et al., 2018; Mazzarotto et al., 2020; Savarese et al., 2020; Yoneda et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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; 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: 31983221, 32039858, 29544605, 25163546, 28045975, 34495297, 22335739, 30535219) - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2019 | The p.R8671* pathogenic mutation (also known as c.26011C>T), located in coding exon 104 of the TTN gene, results from a C to T substitution at nucleotide position 26011. This changes the amino acid from an arginine to a stop codon within coding exon 104. 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, also referred to as p.R8863*(c.26587C>T) and p.R17736* (c.53206C>T), has been detected in dilated cardiomyopathy (DCM), sudden infant death, and early onset atrial fibrillation cohorts (Haas J et al. Eur. Heart J., 2015 May;36:1123-35a; ester DJ et al. J. Am. Coll. Cardiol., 2018 03;71:1217-1227; Choi SH et al. JAMA, 2018 12;320:2354-2364). In one family, this variant was detected in a proband and mother with DCM (Franaszczyk M et al. PLoS ONE, 2017 Jan;12:e0169007). 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
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at