ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.204del (p.Arg69fs) (rs727504872)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000159255 SCV000205952 uncertain significance not specified 2017-08-15 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Arg69fs v ariant in TNNI3 has been observed in our laboratory in one homozygous individual with neonatal onset HCM/DCM. It has been identified in 5/33086 Latino chromosom es by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/ ; dbSNP rs727504872). This variant has been reported in ClinVar variation ID 179 447. This frameshift variant is predicted to alter the protein?s amino acid sequ ence beginning at position 69 and lead to a premature termination codon 8 amino acids downstream. This alteration is then predicted to lead to a truncated or ab sent protein. Although this variant is predicted to be deleterious to the protei n, the variant spectrum of this gene has not been well characterized, and it rem ains unclear if these variant types play a role in disease. In summary, while th ere is some suspicion for a pathogenic role, the clinical significance of the p. Arg69fs variant is uncertain.
GeneDx RCV000223861 SCV000209201 uncertain significance not provided 2017-08-11 criteria provided, single submitter clinical testing While the c.204delG variant has not been published as a pathogenic variant or reported as a benign variant to our knowledge, it has been classified as a likely pathogenic variant by another clinical laboratory in ClinVar (Landrum et al., 2014). The c.204delG variant was not observed in approximately 5,800 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 9.0). This variant causes a shift in reading frame starting at codon Arginine 69, changing it to an Alanine, and creating a premature stop codon at position 8 of the new reading frame, denoted p.Arg69AlafsX8. The c.204delG 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, most of the pathogenic variants reported in TNNI3 to date are missense substitutions that are thought to alter the calcium sensitivity of the troponin complex, leading most often to HCM (Stenson et al., 2014). While other frameshift variants have been reported in HGMD, many of these result in a truncated protein product that may have altered function. The role of true TNNI3 haploinsufficiency in the development of cardiomyopathy, if any, is poorly understood. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001237455 SCV001410216 uncertain significance Hypertrophic cardiomyopathy 2020-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg69Alafs*8) in the TNNI3 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727504872, ExAC 0.04%). This variant has been previously observed in an individual affected with cardiomyopathy or arrhythmia (PMID: 26688388, 31568572, Invitae). ClinVar contains an entry for this variant (Variation ID: 179447). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TNNI3 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Hadassah Hebrew University Medical Center RCV001254648 SCV001430680 pathogenic Dilated cardiomyopathy 2A 2019-06-20 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000223861 SCV001447351 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV001526043 SCV001736312 uncertain significance Cardiomyopathy 2020-07-13 criteria provided, single submitter clinical testing This variant deletes 1 nucleotide in exon 5 of the TNNI3 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with cardiomyopathies or arrhythmia syndromes (PMID: 26688388). This variant has also been reported in homozygosity in a pediatric patient affected with dilated cardiomyopathy (PMID: 31568572). The TNNI3 protein was absent in heart tissue from this patient. Both of his parents were unaffected heterozygous carriers. This variant has been identified in 9/236002 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Clinical relevance of loss-of-function truncation variants in the TNNI3 gene is not clearly established. The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000223861 SCV000280497 likely pathogenic not provided 2013-11-13 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.