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

gnomAD frequency: 0.00001  dbSNP: rs727503506

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham 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	2019-02-04	criteria provided, single submitter	clinical testing	Reported in an adult Chinese male from an HCM cohort who also harbored a nonsense variant in the GLA gene (Zhao et al., 2017); Reported in an Australian proband from an HCM cohort, though patient-specific clinical data were not provided (Burns et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Reported in ClinVar as a variant of uncertain significance and as a likely pathogenic variant, but additional evidence is not available (ClinVar Variant ID# 165520; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28498465, 25086479, 28790153)
Invitae	RCV000233460	SCV000284657	likely pathogenic	Hypertrophic cardiomyopathy	2023-07-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 124 of the TNNI3 protein (p.Glu124Gln). This variant is present in population databases (rs727503506, gnomAD 0.01%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25086479, 28498465, 28790153; Invitae). ClinVar contains an entry for this variant (Variation ID: 165520). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	2023-05-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170618	SCV001352079	uncertain significance	Cardiomyopathy	2019-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 124 of the TNNI3 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in two siblings affected with hypertrophic cardiomyopathy (PMID: 25086479) and in two unrelated individuals affected with hypertrophic cardiomyopathy (PMID: 28498465, 28790153). This variant has also been identified in 2/249260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV002345478	SCV002620606	uncertain significance	Cardiovascular phenotype	2021-12-16	criteria provided, single submitter	clinical testing	The p.E124Q variant (also known as c.370G>C), located in coding exon 6 of the TNNI3 gene, results from a G to C substitution at nucleotide position 370. The glutamic acid at codon 124 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts; however, clinical details were limited and an additional alteration in a cardiac-related gene was identified in one case (Chiou KR et al. J Cardiol, 2015 Mar;65:250-6; Burns C et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]; Ingles J et al. Circ Cardiovasc Genet, 2017 Apr;10:[ePub ahead of print]; Zhao Y et al. Int J Mol Med, 2017 Jul;40:121-129; Mazzarotto F et al. Genet Med, 2019 02;21:284-292). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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"