rs146572907
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.9448C>T(p.Arg3150Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000991 in 1,613,974 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). Synonymous variant affecting the same amino acid position (i.e. R3150R) 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 Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.9448C>T | p.Arg3150Ter | stop_gained | 40/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.9448C>T | p.Arg3150Ter | stop_gained | 40/46 | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.9448C>T | p.Arg3150Ter | stop_gained | 40/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.9448C>T | p.Arg3150Ter | stop_gained | 40/46 | 5 | NM_133379.5 | ||
TTN-AS1 | ENST00000659121.1 | n.1592+3414G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251014Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135646
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461802Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9AN XY: 727204
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74408
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 20, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 26, 2022 | Identified in patients with DCM in the published literature (Corden et al., 2019; Anderson et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32998006, 31251381) - |
Likely pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change creates a premature translational stop signal (p.Arg3150*) 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 (rs146572907, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy (PMID: 32998006; Invitae). ClinVar contains an entry for this variant (Variation ID: 282852). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been reported in individuals affected with autosomal recessive centronuclear myopathy (PMID: 23975875, Invitae internal data). Truncating variants in this region have also been identified in individuals affected with autosomal dominant dilated cardiomyopathy and/or cardio-related conditions (PMID: 27869827, 32964742, Invitae internal data). For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 14, 2022 | The p.R3104* variant (also known as c.9310C>T), located in coding exon 38 of the TTN gene, results from a C to T substitution at nucleotide position 9310. This changes the amino acid from an arginine to a stop codon within coding exon 38. This exon is located in the I-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.R3150*, c.9448C>T, and rs146572907) has been detected in a dilated cardiomyopathy (DCM) cohort and in exome cohorts not selected for the presence of cardiomyopathy; however, clinical details were limited (Georgi B et al. PLoS Genet, 2013 May;9:e1003484; Roberts AM et al. Sci Transl Med. 2015 Jan;7(270):270ra6; Anderson JL et al. Am J Cardiol, 2020 12;137:97-102; Park J et al. Nat Med, 2021 01;27:66-72). 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 majority of available evidence to date, this variant is likely to be pathogenic. - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C2673677:Early-onset myopathy with fatal cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Suma Genomics | - | - - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Genetics and Genomics Program, Sidra Medicine | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at