rs727505284
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.80716C>T(p.Arg26906Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,266 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). 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 Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.80716C>T | p.Arg26906Ter | stop_gained | 326/363 | ENST00000589042.5 | |
TTN-AS1 | NR_038272.1 | n.2044-17156G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.80716C>T | p.Arg26906Ter | stop_gained | 326/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.417-32180G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152010Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000805 AC: 2AN: 248508Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134822
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461256Hom.: 0 Cov.: 37 AF XY: 0.00000413 AC XY: 3AN XY: 726928
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152010Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74228
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 23, 2023 | PP1_strong, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 22, 2021 | Reported in at least two unrelated individuals in association with DCM (Haas et al., 2015; Cuenca et al., 2016); Not observed at significant frequency in large population cohorts (gnomAD); Reported in ClinVar as pathogenic (ClinVar Variant ID 180010; ClinVar); Located in the A-band region of titin, where the majority of truncating pathogenic variants associated with DCM have been reported (Herman et al., 2012).; This variant is associated with the following publications: (PMID: 26899768, 25163546, 22335739) - |
TTN-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 20, 2023 | The TTN c.80716C>T variant is predicted to result in premature protein termination (p.Arg26906*). This variant has been reported in individuals with dilated cardiomyopathy (Haas et al. 2014. PubMed ID: 25163546; Cuenca et al. 2016. PubMed ID: 26899768). Many other truncating variants in this exon have been reported in individuals with cardiomyopathy (https://www.cardiodb.org/titin/titin_exon.php?id=327, Roberts et al. 2015. PubMed ID: 25589632). The c.80716C>T variant is located in the A-band region of the TTN protein and several other truncating variants in this exon have previously been reported to be pathogenic for recessive and dominant TTN-related disorders including dilated cardiomyopathy, centronuclear myopathy, and muscular dystrophy (Human Gene Mutation Database; www.cardiodb.org/titin/titin_exon.php?id=327). RNAseq studies from heart tissue indicate this exon is commonly included in TTN mRNA transcripts (PSI of 100%); however, this analysis was not performed in muscle tissue (Roberts et al. 2015. PMID: 25589632; www.cardiodb.org/titin/titin_exon.php?id=327). TTN truncating variants are reported in 1-2% of presumably healthy individuals and occur more frequently in exons with low PSI values, indicating this variant is more likely to be disease causing (Roberts et al. 2015. PMID: 25589632; Herman et al. 2012. PMID: 22335739).This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-179430143-G-A). In summary, this variant is interpreted as likely pathogenic for TTN-related disorders. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg26906*) 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 (rs727505284, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 25163546, 26899768; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.C54097T (p.R18033X) and c.53521C>T (p.Arg17841*). ClinVar contains an entry for this variant (Variation ID: 180010). 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. - |
Primary dilated cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 02, 2017 | The p.Arg24338X variant in TTN has been identified in at least 3 individuals wit h DCM and segregated with disease in 5 affected relatives (Haas 2015, Cuenca 201 6, LMM data). It has been identified in 2/30756 South Asian chromosomes by the G enome Aggregation Database (gnomAD, http://exac.broadinstitute.org). This varian t is present in ClinVar (Variation ID: 180010). This nonsense variant leads to a premature termination codon at position 24338, which is predicted to lead to a truncated or absent protein. Nonsense and other truncating variants in TTN are s trongly associated with DCM if they are located in the exons encoding for the A- band (Herman 2012, Pugh 2014) and/or are located in an exon that is highly expre ssed in the heart (Roberts 2015). The p.Arg24338X variant is located in A-band i n the highly expressed exon 275. In summary, this variant meets criteria to be c lassified as pathogenic for DCM in an autosomal dominant manner. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 23, 2021 | The p.R17841* pathogenic mutation (also known as c.53521C>T), located in coding exon 153 of the TTN gene, results from a C to T substitution at nucleotide position 53521. 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 mutation (also described as NM_133437 p.R18033X) has been reported in individuals with dilated cardiomyopathy (DCM), including several affected relatives from a single family (Haas J et al. Eur Heart J, 2015 May;36:1123-35a; Cuenca S et al. J Heart Lung Transplant, 2016 05;35:625-35). In addition to the clinical data presented in the literature, 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. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 24, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at