rs140743001
Variant summary
Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.44272C>T(p.Arg14758*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,770 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. R14758R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 stop_gained
Scores
Clinical Significance
Conservation
Publications
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ACMG classification
Our verdict: Likely_pathogenic. The variant received 9 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_001267550.2. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | NM_001267550.2 | MANE Select | c.44272C>T | p.Arg14758* | stop_gained | Exon 239 of 363 | NP_001254479.2 | ||
| TTN | NM_001256850.1 | c.39349C>T | p.Arg13117* | stop_gained | Exon 189 of 313 | NP_001243779.1 | |||
| TTN | NM_133378.4 | c.36568C>T | p.Arg12190* | stop_gained | Exon 188 of 312 | NP_596869.4 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| TTN | ENST00000589042.5 | TSL:5 MANE Select | c.44272C>T | p.Arg14758* | stop_gained | Exon 239 of 363 | ENSP00000467141.1 | ||
| TTN | ENST00000446966.2 | TSL:1 | c.44116C>T | p.Arg14706* | stop_gained | Exon 237 of 361 | ENSP00000408004.2 | ||
| TTN | ENST00000436599.2 | TSL:1 | c.43996C>T | p.Arg14666* | stop_gained | Exon 237 of 361 | ENSP00000405517.2 |
Frequencies
GnomAD3 genomes 0.0000198 AC: 3AN: 151846Hom.: 0 Cov.: 33 show subpopulations
GnomAD2 exomes AF: 0.00000805 AC: 2AN: 248384 AF XY: 0.00000742 show subpopulations
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460806Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 726678 show subpopulations
Age Distribution
GnomAD4 genome 0.0000197 AC: 3AN: 151964Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74236 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:4Uncertain:1
Located in a specific region of the I-band within TTN for which truncating variants are significantly associated with autosomal dominant cardiomyopathy and also with autosomal recessive skeletal myopathies (PMID: 27625338, 27869827, 32778822); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22335739, 24503780, 30333491, 33874732, 33106378, 31737537, 33500567, 31112426, 33996946, 27532257, 27625338, 27869827, 32778822, 37728764, 31691645, 36264615, 37652022)
TTN: PVS1:Strong, PM2, PS4:Moderate
Dilated cardiomyopathy 1G Pathogenic:3
The TTN c.44272C>T (p.Arg14758Ter) is a nonsense variant, located in exon 239 of the meta transcript of titin within the I-band, which is highly expressed in cardiac tissue (PMID:25589632). In a meta-analysis of TTN truncating variants in DCM patients and controls, variants in this region were associated with a significantly increased risk of developing DCM (odds ratio 19.5) (PMID:27869827). The p.Arg14758Ter variant has been reported in the literature in one patient with dilated cardiomyopathy (PMID:27532257). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000026 in the Total population (version 3.1.2). Based on the available evidence the c.44272C>T (p.Arg14758Ter) variant is classified as likely pathogenic for dilated cardiomyopathy.
Cardiovascular phenotype Pathogenic:2
PVS1, PS4_mod, PM2, PP5
The p.R5693* variant (also known as c.17077C>T), located in coding exon 66 of the TTN gene, results from a C to T substitution at nucleotide position 17077. This changes the amino acid from an arginine to a stop codon within coding exon 66. 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.R14758X, c.44272C>T and 2:179494977G>A) has been detected in cohorts reported to have atrial fibrillation, peripartum cardiomyopathy, left ventricular non-compaction cardiomyopathy, dilated cardiomyopathy (DCM) or who underwent genetic testing for DCM (Walsh R et al. Genet. Med., 2017 02;19:192-203; Vissing CR et al. J Med Genet. 2021 Dec;58(12):832-841; Goli R et al. Circulation. 2021 May;143(19):1852-1862; Mazzarotto F et al. Genet Med. 2021 May;23(5):856-864). 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). As such, this alteration is classified as likely pathogenic.
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
This sequence change creates a premature translational stop signal (p.Arg14758*) 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 (rs140743001, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 27532257, 31737537, 33500567, 33874732; internal data). ClinVar contains an entry for this variant (Variation ID: 202367). 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, 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, internal data). For these reasons, this variant has been classified as Pathogenic.
Cardiomyopathy Pathogenic:1
The c.39349C>T variant in TTN (NM_001256850.1) leads to premature stop codon at position 13117, which is predicted to lead to a truncated or absent protein. This variant has also been referred to as c.44272C>T, p.R14758X using alternate nomenclature. It was identified in 2/248384 (0.0008%) of alleles tested from control populations in the Genome Aggregation Database (gnomAD), was reported in 0.003% of Admixed American individuals, and is considered to be a rare variant. It has been previously reported in >5 apparently unrelated individuals with dilated, left ventricular non-compaction, atrial fibrillation, peripartum, or unspecified cardiomyopathy (PMID 27532257, 31737537, 33106378, 33996946, 36264615, 30333491, 33874732, ClinVar database, CHEO internal database). This variant is located in the proximal I-band in a highly expressed exon, where Titin truncating variants are very strongly associated with dilated cardiomyopathy (PMID 27625338, 26439713, 25589632). This variant is listed in ClinVar (VCV000202367). Based on the above information, we categorize this variant as pathogenic.
Autosomal recessive titinopathy Pathogenic:1
Variant summary: TTN c.36568C>T (p.Arg12190X; also known as c.44272C>T; p.Arg14758X on NM_001267550) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Loss of function variants in all TTN bands are strongly associated with a spectrum of autosomal recessive titinopathies when exon expression (proportion spliced in, PSI, 1=complete expression) in skeletal muscle is >0.1 (PMID: 36977548, 39198997, 29598826, 32778822, 29691892, 33449170, 36977548, internal data). In contrast, loss of function variants in all TTN bands are only strongly associated with autosomal dominant TTN-related cardiomyopathies if located in exons constitutively expressed (PSI >0.9) in cardiac muscle, excluding extreme C-terminal exons 359-363 (PMID: 25589632, 31216868, 32964742, 34662387, 27869827, Shetty et al., Nat Cardiovasc Res 2024, cardiodb.org, internal data). This variant has a maximum skeletal muscle PSI of 0.959 and a maximum cardiac muscle PSI of 1.0. The variant allele was found at a frequency of 8.1e-06 in 248384 control chromosomes (gnomAD). c.36568C>T has been reported in the literature in individuals affected with autosomal dominant cardiac conditions and autosomal recessive TTN-related conditions (examples: Vissing_JMG_2021, Goli_Circulation_2021, Xiao_FCM_2021, internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33106378, 33874732, 33996946). ClinVar contains an entry for this variant (Variation ID: 202367). Based on the evidence outlined above, the variant was classified as likely pathogenic for both autosomal dominant and autosomal recessive TTN-related conditions.
Primary dilated cardiomyopathy Pathogenic:1
The p.Arg12190X variant in TTN has been identified by our laboratory in 1 Caucas ian individual with DCM and 1 Caucasian individual with LVNC (LMM data). This va riant has also been identified in 1/67564 European chromosomes by the Exome Aggr egation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs140743001). Th is nonsense variant leads to a premature termination codon at position 12190, wh ich is predicted to lead to a truncated or absent protein. Nonsense and other tr uncating variants in TTN are strongly associated with DCM if they are located in the exons encoding for the A-band (Herman 2012, Pugh 2014) and/or are located i n an exon that is highly expressed in the heart (Roberts 2015). The p.Arg12190X variant is located in I-band in the highly expressed exon 188. In summary, alth ough additional studies are required to fully establish its clinical significanc e, the p.Arg12190X variant is likely pathogenic.
not specified Uncertain:1
The c.36568C>T sequence change results in the creation of a premature stop codon at amino acid position 12190, p.Arg12190*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated TTN protein with potentially abnormal function. This variant is present in 2 individuals in gnomAD with an overall population frequency of 0.008% (rs140743001). This variant has also been reported in an individual with dilated cardiomyopathy (PMID: 27532257). This variant is present in ClinVar and has been classified as either a variant of unknown significance or likely pathogenic by several clinical laboratories (Variation ID: 202367). The Arg12190* variant is located in one of the constitutive exons in the distal I-band region. Truncating variants in this region have been reported in individuals with autosomal recessive centronuclear myopathy (PMID: 23975875) however truncating TTN variants have been reported in approximately 3% of control alleles (PMIDs: 22335739, 26701604). Due to these contrasting evidences, the clinical significance of the p.Arg12190* change remains unknown at this time.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at