rs794729265
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.50170C>T(p.Arg16724Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000248 in 1,612,288 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. R16724R) 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.50170C>T | p.Arg16724Ter | stop_gained | 266/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.50170C>T | p.Arg16724Ter | stop_gained | 266/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.502+14674G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151856Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460432Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 726514
GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151856Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74154
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2023 | For these reasons, this variant has been classified as Pathogenic. 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). ClinVar contains an entry for this variant (Variation ID: 202378). This premature translational stop signal has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy and dilated cardiomyopathy (PMID: 25163546, 25589632, 28877744). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg16724*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 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; 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); Reported in several individuals with DCM and in one case of early-onset atrial fibrillation (Haas et al., 2015; Roberts et al., 2015; Ramchand et al., 2020; Mazzarotto et al., 2020; Ahlberg et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30333491, 31931689, 31983221, 25589632, 28877744, 22335739, 25163546) - |
Primary dilated cardiomyopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | Oct 08, 2014 | This TTN truncating variant (TTNtv) was identified in three individuals in this cohort and is located in an exon that is highly expressed in the heart. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 23, 2022 | The p.R7659* pathogenic mutation (also known as c.22975C>T), located in coding exon 93 of the TTN gene, results from a C to T substitution at nucleotide position 22975. This changes the amino acid from an arginine to a stop codon within coding exon 93. 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.R16724X and p.R7851X) has been detected in individuals from dilated cardiomyopathy (DCM) cohorts (Roberts AM et al. Sci Transl Med, 2015 Jan;7:270ra6; Haas J et al. Eur Heart J, 2015 May;36:1123-35a). 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 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