rs886042995
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5
The NM_001267550.2(TTN):c.15922C>T(p.Arg5308Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000242 in 1,613,608 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. R5308R) 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.15922C>T | p.Arg5308Ter | stop_gained | 54/363 | ENST00000589042.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.15922C>T | p.Arg5308Ter | stop_gained | 54/363 | 5 | NM_001267550.2 | P1 | |
TTN-AS1 | ENST00000659121.1 | n.503-1133G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152078Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248646Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134860
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461530Hom.: 0 Cov.: 36 AF XY: 0.0000234 AC XY: 17AN XY: 727046
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152078Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74270
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 02, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 19, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2023 | Identified in a patient with early onset atrial fibrillation (Choi et al., 2018) and in a patient with left ventricular non-compaction who also harbored variants in the DSP and NKX2-5 genes (Ross et al., 2020); please note Ross et al. describe the variant as p.Arg4991Ter due to use of alternate nomenclature; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; Located in the I-band region that does not affect one of the constitutive exons; studies suggest that truncating variants affecting constitutive exons throughout the TTN gene are significantly associated with DCM (Deo,2016; Schafer et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 35177841, 36495114, 30535219, 33082984, 27625338, 27869827, 32778822) - |
Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change creates a premature translational stop signal (p.Arg5308*) in the TTN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated TTN protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with atrial fibrillation and/or TTN-related myopathies (PMID: 30535219, 32778822, 33449170, 36495114). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 284964). This variant is located in the I band of TTN (PMID: 25589632). Truncating variants in this region have been shown to be highly prevalent in the general population and unaffected individuals (PMID: 26701604, 22335739). However, 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. - |
Early-onset myopathy with fatal cardiomyopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 29, 2019 | This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. - |
TTN-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Nov 05, 2018 | The TTN c.12190C>T (p.Arg4064Ter) variant is a stop-gained variant. A literature search was performed for the gene, cDNA change, and amino acid change. No publications were found based on this search. This variant is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the variant frequency, disease prevalence, disease penetrance, and inheritance mode, this variant could not be ruled out of causing disease. Due to the potential impact of stop-gained variants and the lack of clarifying evidence, this variant is classified as a variant of unknown significance but suspicious for pathogenicity for TTN-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at