ClinVar Miner

Submissions for variant NM_000363.4(TNNI3):c.204delG (p.Arg69Alafs) (rs727504872)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
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 variant 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 chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs727504872). This variant has been reported in ClinVar variation ID 179447. This frameshift variant is predicted to alter the protein’s amino acid sequence 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 absent protein. Although this variant is predicted to be deleterious to the protein, the variant spectrum of this gene has not been well characterized, and it remains unclear if these variant types play a role in disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg69fs variant is uncertain.
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

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