rs778172350
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1
The NM_001267550.2(TTN):βc.11183_11184insGβ(p.Leu3729ThrfsTer9) variant causes a frameshift change. The variant allele was found at a frequency of 0.000304 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. G3728G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001267550.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TTN | NM_001267550.2 | c.11183_11184insG | p.Leu3729ThrfsTer9 | frameshift_variant | 46/363 | ENST00000589042.5 | |
TTN | NM_133379.5 | c.10303+2691_10303+2692insG | intron_variant | ENST00000360870.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TTN | ENST00000589042.5 | c.11183_11184insG | p.Leu3729ThrfsTer9 | frameshift_variant | 46/363 | 5 | NM_001267550.2 | P1 | |
TTN | ENST00000360870.10 | c.10303+2691_10303+2692insG | intron_variant | 5 | NM_133379.5 | ||||
TTN-AS1 | ENST00000659121.1 | n.1252dup | non_coding_transcript_exon_variant | 7/13 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000105 AC: 26AN: 248776Hom.: 0 AF XY: 0.0000815 AC XY: 11AN XY: 134932
GnomAD4 exome AF: 0.000318 AC: 465AN: 1461510Hom.: 0 Cov.: 33 AF XY: 0.000283 AC XY: 206AN XY: 727048
GnomAD4 genome AF: 0.000164 AC: 25AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74488
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | TTN: PVS1:Moderate, PS4:Supporting - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jun 24, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 17, 2014 | c.10670dupG: p.Leu3558ThrfsX9 (L3558TfsX9) in exon 44 of the TTN gene (#NM_133437.3). The normal sequence with the base that is duplicated in braces is: CAAG{G}ACTA. The c.10670dupG variant has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. This variant causes a shift in reading frame starting at codon Leucine 3558, changing it to a Threonine, and creating a premature stop codon at position 9 of the new reading frame, denoted p.Leu3558ThrfsX9. This variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. However, c.10670dupG is located in an alternate transcript of the TTN gene where no disease-causing mutations have been reported.With the clinical and molecular information available at this time, we cannot definitively determine if c.10670dupG is a disease-causing mutation or a rare benign variant. The variant is found in DCM-CRDM panel(s). - |
Primary dilated cardiomyopathy Uncertain:2
Uncertain significance, criteria provided, single submitter | research | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | Oct 08, 2014 | This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with low levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. - |
Uncertain significance, criteria provided, single submitter | research | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | Oct 08, 2014 | This TTN truncating variant (TTNtv) was identified in one individual in this cohort and is located in an exon with low levels of cardiac expression. In the seven cohorts assessed, TTNtv were found in 14% of ambulant DCM, 22% end-stage or familial DCM, and 2% controls. Heterozygous nonsense, frameshift and canonical splice-disrupting variants found in constitutive and other highly utilised exons are highly likely to be pathogenic when identified in individuals with phenotypically confirmed DCM. TTNtv found incidentally in healthy individuals (excluding familial assessment of DCM relatives) are thought to have low penetrance, particularly when identified in exons that are not constitutively expressed in the heart. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 24, 2022 | Variant summary: TTN NM_133378.4: c.10303+2691dupG alters a concerved nucleotide located at a position not widely known to affect splicing. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant is also annotated as NM_001267550.1: c.11183dupG (p.Leu3729fs) in exon 46 of meta transcript. This exon is considered as a low expression exon with a percentage spliced in (PSI) score of 4% and is therefore not considered as a constitutively expressed exon of critical relevance to TTN function. TTN truncating variants in this exon are considered to be tolerated and therefore not relevant to any of the penetrant TTN-related disorder phenotypes. The variant allele was found at a frequency of 0.0001 in 248776 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in TTN causing Cardiomyopathy (0.0001 vs 0.00063), allowing no conclusion about variant significance. c.10303+2691dupG has been reported as c.11183dupG in the literature in a variety of settings such as, controls and individuals with heart failure from the UK biobank cohort (example, Choi_2020), one Dilated Cardiomyopathy (DCM) proband from a cohort that underwent reverse-parent offspring analysis (example, Jansen_2019), in one individual from a cohort of patients with early-onset artial fibrillation (example, Yoneda_2021). These report(s) do not provide unequivocal conclusions about association of the variant with penetrant TTN-related phenotypes of Dilated Cardiomyopathy/Limb-Girdle Muscular Dystrophy, Type 2J. At-least one co-occurrence with another pathogenic variant(s) has been reported in an individual from a cohort with early-onset Atrial Fibrillation (AF diagnosed before the age of 66 years)(Yoneda_2021, MYH7 c.1988G>A, p.Arg663His), although the specific clinical details were not reported. This provides supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 26, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at