Submissions for variant NM_000363.5(TNNI3):c.497C>T (p.Ser166Phe)

gnomAD frequency: 0.00001  dbSNP: rs727504242

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628993	SCV000203863	likely pathogenic	Hypertrophic cardiomyopathy	2020-05-25	criteria provided, single submitter	clinical testing	The p.Ser166Phe variant in TNNI3 has been reported at least 10 individuals with HCM and 1 infant with sudden infant death (Van Driest 2003, Mogensen 2004, van den Wigngaard 2011, Brion 2012, LMM data). One of these individuals also carried a pathogenic variant in MYBPC3 and had an early age of disease onset (Van Driest 2004). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID: 177630) and has been identified in 0.002% (2/113184) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org/). In vitro functional studies support an impact on protein function (Liu 2012). Additionally, computational prediction tools and conservation analyses are consistent with pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HCM. ACMG/AMP Criteria applied:PM2, PS4_Moderate, PP3, PS3_Supporting.
GeneDx	RCV000159230	SCV000209176	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrated that p.(S166F) significantly increased the calcium sensitivity and slowed the rate of calcium dissociation from the Troponin complex, and may influence TnC-TnI interactions (Liu et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11121119, 24510615, 31737537, 22361390, 22675533, 15607392, 15519027, 12860912, 12974739, 21839045, 26526134, 19914256, 26914223, 27532257, 30847666, 31447099, 33662488, 36411388, 35626289, 35470684, 21533915)
Invitae	RCV000628993	SCV000749903	pathogenic	Hypertrophic cardiomyopathy	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 166 of the TNNI3 protein (p.Ser166Phe). This variant is present in population databases (rs727504242, gnomAD 0.002%). This missense change has been observed in individuals with autosomal dominant hypertrophic cardiomyopathy (PMID: 21533915). ClinVar contains an entry for this variant (Variation ID: 177630). 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 disruptive. Experimental studies have shown that this missense change affects TNNI3 function (PMID: 22675533). For these reasons, this variant has been classified as Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709766	SCV000840075	likely pathogenic	Hypertrophic cardiomyopathy 7	2018-01-18	criteria provided, single submitter	clinical testing	The c.497C>T (p.Ser166Phe) variant has been reported in several patients with hypertrophic cardiomyopathy (HCM) [PMID 21533915, 12974739, 26914223]. One of the reported patient also carried a variant in MYH7 (p.Cys905Phe) [PMID 12974739]. The variant was detected in 4/1,040 patients in the Netherland and is consider a founder mutation in this population [PMID 21533915]. Functional assays showed that this change alters the calcium binding properties of the Tn complex [PMID 22675533]. This variant was observed in only one individual at the heterozygous state in the ExAC population database (http://exac.broadinstitute.org/variant/19-55665450-G-A).Serine at position 166 of the TNNI3 protein is conserved in mammals and while not clinically validated, computer-based algorithms (SIFT and Polyphen-2) predict this p.Ser166Phe change to be deleterious. This variant is thus classified as likely pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159230	SCV001762182	pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798495	SCV002042738	pathogenic	Cardiomyopathy	2023-06-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000159230	SCV002103282	likely pathogenic	not provided	2021-09-09	criteria provided, single submitter	clinical testing	PM1, PM2_supporting, PS3_supporting, PS4_moderate
AiLife Diagnostics, AiLife Diagnostics	RCV000159230	SCV002502107	likely pathogenic	not provided	2021-07-20	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000709766	SCV002580479	likely pathogenic	Hypertrophic cardiomyopathy 7	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336315	SCV002644006	likely pathogenic	Cardiovascular phenotype	2024-03-15	criteria provided, single submitter	clinical testing	The p.S166F variant (also known as c.497C>T), located in coding exon 7 of the TNNI3 gene, results from a C to T substitution at nucleotide position 497. The serine at codon 166 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been reported in hypertrophic cardiomyopathy (HCM) cohorts and has been described as a Finnish founder mutation (Erdmann J, Clin. Genet. 2003 Oct; 64(4):339-49; Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Mogensen J, J. Am. Coll. Cardiol. 2004 Dec; 44(12):2315-25; van den Wijngaard A, Neth Heart J 2011 Aug; 19(7-8):344-51; Maron BJ, Heart Rhythm 2012 Jan;9(1):57-63). In some of the reported cases, the p.S166F alteration was seen in individuals who also had variants in other cardiac-related genes (Erdmann J, Clin. Genet. 2003 Oct; 64(4):339-49; Van Driest SL, J. Am. Coll. Cardiol. 2004 Nov; 44(9):1903-10; Maron BJ, Heart Rhythm 2012 Jan;9(1):57-63). In addition, this alteration has been shown to have an impact on protein function ( Liu B, PLoS ONE 2012 Jun; 7(6):e38259). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic for autosomal dominant TNNI3-related cardiomyopathy; however, its clinical significance for autosomal recessive TNNI3-related dilated cardiomyopathy is uncertain.
Color Diagnostics, LLC DBA Color Health	RCV001798495	SCV004359897	likely pathogenic	Cardiomyopathy	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 166 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). One in-vitro functional study showed that this variant led to an increase in calcium sensitivity as well as a decrease in the rate of calcium dissociation from the troponin complex (PMID: 22675533). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 12974739, 15519027, 15607392 , 21533915, 21839045, 15519027, 27532257, 30847666, 31737537, 33662488, 35626289). One of these individuals also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 21839045). This variant has also been reported in an individual affected with atrioventricular block (PMID: 35470684), in a case of sudden infant death (PMID: 22361390), and in an individual affected with juvenile ischemic stroke (PMID: 36411388). This variant has been identified in 2/249054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
All of Us Research Program, National Institutes of Health	RCV000628993	SCV004822601	likely pathogenic	Hypertrophic cardiomyopathy	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 166 in the C-terminal mobile domain of the TNNI3 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). One in-vitro functional study showed that this variant led to an increase in calcium sensitivity as well as a decrease in the rate of calcium dissociation from the troponin complex (PMID: 22675533). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12860912, 12974739, 15519027, 15607392 , 21533915, 21839045, 15519027, 27532257, 30847666, 31737537, 33662488). One of these individuals also carried a pathogenic variant in the MYBPC3 gene (PMID: 15519027, 21839045). This variant has also been reported in an individual affected with atrioventricular block (PMID: 35470684) and in a case of sudden infant death (PMID: 22361390). This variant has been identified in 2/249054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University	RCV000159230	SCV000280509	likely pathogenic	not provided	2014-04-11	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 variant has been seen in at least 9 unrelated published cases of HCM (see details below). The testing lab also states in their report that they have seen this particular variant in multiple unrelated individuals tested for HCM. Unfortunately, there is no segregation data presented in any of these studies. 2 of these 9 patients identified with this p.S166F variant also harbored another variant in a sarcomeric gene (including one novel missense variant in MYH7, and one nonsense variant in MYBPC3). Erdmann J et al. 2003 screened for mutations in 6 sarcomeric genes (MYBPC3, MYH7, TNNT2, TPM1, TNNI3, and TNNC1) in 108 patients with clinical diagnosis of HCM. This particular p.S166F variant was identified in 1 individual with HCM, though notably this individual also carried a novel missense variant in MYH7. p.S166F in TNNI3 was absent from 50 German controls. No segregation data is presented. While the authors note the highly conserved residue 166 and change in charge, they conclude that there is no proof that both missense variants (if any) are disease causing. Van Driest S et al. 2003 identified p.S166F in 3 unrelated patients with HCM. There was no family history or segregation data available. This variant was absent from 200 healthy controls from Coriell (100 African Americans and 100 European Americans). The same group subsequently screened this same cohort for mutations in MYBPC3, and identified an individual with HCM with both p.S166F in TNNI3 as well as a nonsense variant in MYBPC3. Given that this was the same cohort as their 2003 paper, the total unrelated HCM patients with the S166F variant from the Van Driest group appears to be 3, though notably with one occurring in the presence of another (likely pathogenic) variant. Mogensen J et al. 2004 identified p.S166F in 1 proband with HCM in a UK cohort and this proband’s clinically unaffected sister (though no ages or details are provided). Absent from 75 Caucasian controls. No segregation data presented. Additionally, the authors only screened this cohort of HCM patients for mutations in TNNI3.Finally, Van den Wijngaard A et al. 2011 identified this variant in 4 unrelated patients with HCM in the Netherlands, though no segregation data available and weak methodology in that sounds like they only screened TNNI3 in this large cohort of cardiomyopathy patients. In silico analysis with PolyPhen-2 predicts the variant to be possibly damaging, and Mutation Taster considers this variant disease-causing. Ser166Phe results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Phenylalanine. The Serine at codon 166 is completely conserved across species, as are neighboring amino acids. This variant occurs in exon 7 of 8 coding exons. Other variants have been reported in association with disease at nearby codons (Lys164Thr, Leu167Pro). One paper found that the majority of TNNI3 mutations as of 2011 were identified in exons 7 and 8, encoding domains interacting with cardiac actin (ACTC1) and cardiac troponin C (TNNC1).Disease-causing variants in MYBPC3 and MYH7 are most common in HCM, accounting for 20%-45% and 15%-20% of the disease, respectively. Cardiac troponin T type 2 (TNNT2) and troponin I type 3 (TNNI3) each account for ~5%. Variation in other sarcomere genes is less frequent. In total the variant has not been seen in approximately 6,350 published controls and individuals from publicly available population datasets (this includes 350 published controls from the literature, and individuals from publicly available population datasets). There is no variation at codon 166 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls in TNNI3 on approximately 4200 Caucasian and 2000 African American individuals (as of 8/6/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/6/13).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000159230	SCV001741336	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000159230	SCV001920116	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000159230	SCV001957991	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000159230	SCV001967521	pathogenic	not provided		no assertion criteria provided	clinical testing