2-178617857-G-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_001267550.2(TTN):c.47494C>T(p.Arg15832Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000558 in 1,612,382 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R15832R) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.47494C>T | p.Arg15832Ter | stop_gained | 253/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.47494C>T | p.Arg15832Ter | stop_gained | 253/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+20176G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151836Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248042Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134558
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460546Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 726606
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151836Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74134
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Aug 18, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 14, 2023 | 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; Observed with an additional pathogenic variant in an individual with muscle weakness referred for genetic testing at GeneDx and testing of one parent suggests the variants are likely present on opposite alleles (in trans); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 35177841, 30535219, 31317183, 32815318, 34495297, 25589632, 23975875) - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg15832*) 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 (rs751746401, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with autosomal dominant dilated cardiomyopathy and/or autosomal recessive centronuclear myopathy (PMID: 31317183, 32815318; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Arg6767*. ClinVar contains an entry for this variant (Variation ID: 264517). 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. - |
Cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 25, 2020 | - - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 27, 2023 | The p.R6767* pathogenic mutation (also known as c.20299C>T), located in coding exon 80 of the TTN gene, results from a C to T substitution at nucleotide position 20299. This changes an amino acid from an arginine to a stop codon within coding exon 80. 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 (c.47494C>T, p.R15832X)) has been reported in early-onset atrial fibrillation and dilated cardiomyopathy cohorts (Choi SH et al. JAMA, 2018 12;320:2354-2364; Augusto JB et al. Eur Heart J Cardiovasc Imaging, 2019 Jul). 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 Jan;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