ClinVar Miner

Submissions for variant NM_000363.5(TNNI3):c.370G>C (p.Glu124Gln) (rs727503506)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000152086 SCV000200726 uncertain significance not specified 2013-10-14 criteria provided, single submitter clinical testing The Glu124Gln variant in TNNI3 has not been previously reported in individuals w ith cardiomyopathy. Glutamic acid (Glu) at position 124 is highly conserved in m ammals and across most evolutionarily distant species and the change to glutamin e (Gln) was predicted to be pathogenic using a computational tool clinically val idated by our laboratory. This tool's pathogenic prediction is estimated to be c orrect 94% of the time (Jordan 2011). Additional computational analyses (biochem ical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional info rmation is needed to fully assess the clinical significance of this variant.
GeneDx RCV000766926 SCV000209164 uncertain significance not provided 2016-05-23 criteria provided, single submitter clinical testing The E124Q variant in the TNNI3 gene was identified in one proband and two of his affected relatives in a study of 38 Taiwanese probands diagnosed with HCM (Chiou et al., 2014). E124Q was not observed in approximately 6,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E124Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Glutamic acid are tolerated across species. Nevertheless, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV000233460 SCV000284657 likely pathogenic Hypertrophic cardiomyopathy 2020-08-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 124 of the TNNI3 protein (p.Glu124Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is present in population databases (rs727503506, ExAC 0.01%). This variant has been reported in two unrelated individuals (PMID: 28790153, 28498465) and also in two brothers affected with hypertrophic cardiomyopathy with a third relative who carried the variant but was unaffected (PMID: 25086479). ClinVar contains an entry for this variant (Variation ID: 165520). A computational algorithm designed to assess the pathogenicity of variants in TNNI3 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious; algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170618 SCV001333208 uncertain significance Cardiomyopathy 2018-06-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV001170618 SCV001352079 uncertain significance Cardiomyopathy 2019-05-01 criteria provided, single submitter clinical testing
Agnes Ginges Centre for Molecular Cardiology,Centenary Institute RCV000233460 SCV001156308 uncertain significance Hypertrophic cardiomyopathy 2020-04-07 no assertion criteria provided research The TNNI3 Glu124Gln has been previously identified in a Taiwanese HCM proband, that suffered a resuscitated cardiac arrest, the variant segregated to an affected sibling (Chiou KR, et al., 2015). It has also been identified in 4 HCM probands by Genedx (personal communication) and 1 HCM proband of Asian descent by the Laboratory of Molecular Medicine (personal communication). The variant has been seen as a singleton event in the East Asian sub-population in the Exome Aggregation Consortium dataset (MAF=0.000008; http://exac.broadinstitute.org/). We identified this variant in HCM proband (Burns et al., 2017; Ingles et al., 2017). The proband is of Chinese descent and has a family history of HCM, however segregation was not possible. Computational tools PolyPhen2, PolyPhen-HCM and MutationTaster predict this variant to be deleterious, however SIFT predicts this variant to be "Tolerated". Based on the adapted ACMG guidelines (Kelly MA, et al., 2018) the variant is rare in the general population (PM2) and has been identified in at least 7 HCM probands (PS4_moderate), therefore we classify TNNI3 Glu124Gln as a variant of "uncertain significance"

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