rs774411587
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001267550.2(TTN):c.79294C>T(p.Arg26432Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,212 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 (★★). 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.79294C>T | p.Arg26432Ter | stop_gained | 326/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2044-15734G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.79294C>T | p.Arg26432Ter | stop_gained | 326/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-30758G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000807 AC: 2AN: 247898Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134534
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461212Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 726902
GnomAD4 genome ? Cov.: 33
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 | Jan 22, 2024 | This sequence change creates a premature translational stop signal (p.Arg26432*) 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 (rs774411587, gnomAD 0.006%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 466659). 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. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 06, 2022 | The p.R17367* variant (also known as c.52099C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 52099. This changes the amino acid from an arginine to a stop codon within coding exon 153. 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 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at