ClinVar Miner

Submissions for variant NM_001267550.2(TTN):c.11183dup (p.Leu3729fs) (rs778172350)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000184376 SCV000051224 uncertain significance not provided 2013-06-24 criteria provided, single submitter research
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209565 SCV000189728 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000209565 SCV000189798 uncertain significance Primary dilated cardiomyopathy 2014-10-08 criteria provided, single submitter research 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.
GeneDx RCV000184376 SCV000237001 uncertain significance not provided 2014-02-17 criteria provided, single submitter clinical testing 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).
CeGaT Praxis fuer Humangenetik Tuebingen RCV000184376 SCV000493693 likely pathogenic not provided 2016-07-31 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769096 SCV000900469 uncertain significance Cardiomyopathy 2017-06-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001289915 SCV001477917 uncertain significance none provided 2020-06-01 criteria provided, single submitter clinical testing The TTN c.11183dupG; p.Leu3729Thrfs*9 variant (rs778172350), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 202507). This variant is found in the general population with an overall allele frequency of 0.011% (31/280174 alleles) in the Genome Aggregation Database. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. However, the exon carrying this variant is estimated to be present in only 4% of TTN transcripts (Roberts 2015). Thus, only a small portion of TTN mRNAs would be subject to NMD due to this variant, and it is unclear if this proportion would be clinically significant. Given the lack of clinical and functional data, the significance of the c.11183dupG variant is uncertain at this time. References: Roberts AM, Ware JS, Herman DS, et al. Integrated allelic, transcriptional, and phenomic dissection of the cardiac effects of titin truncations in health and disease. Sci Transl Med. 2015;7(270):270ra6.

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