ClinVar Miner

Submissions for variant NM_000363.4(TNNI3):c.497C>T (p.Ser166Phe) (rs727504242)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159230 SCV000209176 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing The S166F variant in the TNNI3 gene has been reported multiple times in association with HCM and has been observed in multiple unrelated individuals referred for HCM genetic testing at GeneDx (Erdmann et al., 2003; Van Driest et al., 2003; Van Driest et al., 2004; Mogensen et al., 2004; Van den Wijngaard et al., 2011; Maron et al., 2012; Kapplinger et al., 2014). However, in three individuals, the S166F variant was observed in combination with a second pathogenic variant in a sarcomere gene (Erdmann et al., 2003; Van Driest et al., 2004; Maron et al., 2012). Nevertheless, several studies have reported S166F as the only identifiable variant in patients with HCM (Mogensen et al., 2004; Van den Wijngaard et al., 2011). Van den Wijngaard et al. (2011) identified S166F in three families with HCM and determined it is a founder mutation in the Dutch population. Functional studies demonstrated that S166F significantly increased the calcium sensitivity and slowed the rate of calcium dissociation from the Troponin complex (Liu et al 2012). The authors suggest that, since this variant is located close to the switch region that binds to the hydrophobic pocket of the regulatory domain of Troponin C (TnC), it may influence TnC-TnI interactions (Liu et al., 2012). The S166F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Furthermore, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Other pathogenic and likely pathogenic missense variants in nearby residues (R162W, R162Q, R170Q, R170W) have been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014). Considering all publications, the S166F variant was absent from at least 500 control alleles (Erdmann et al., 2003; Van Driest et al., 2003; Mogensen et al., 2004). In addition, the S166F variant has not been observed at a significant frequency in large population cohorts (Lek et al., 2016). In summary, S166F in the TNNI3 gene is interpreted as a pathogenic variant.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709766 SCV000840075 likely pathogenic Familial 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.
Invitae RCV000628993 SCV000749903 likely pathogenic Hypertrophic cardiomyopathy 2018-01-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 166 of the TNNI3 protein (p.Ser166Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs727504242, ExAC 0.002%). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (HCM) (PMID: 27532257, 21533915 , 15607392). ClinVar contains an entry for this variant (Variation ID: 177630). Experimental studies have shown that this missense change disrupts tropnonin complex function decreasing the calcium binding affinity and rate of disassociation from the thin filament (PMID: 22675533). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154210 SCV000203863 uncertain significance not specified 2017-08-06 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ser166Phe variant in TNNI3 has been reported in 9 individuals with HCM and 1 case of SIDs (Van Driest 2003, Mogensen 2004, van den Wigngaard 2011, Brion 2012). However, in 2 of the HCM cases, variants in other HCM-associated genes were also identified (Erdmann 2003, Van Driest 2004). In vitro functional studies provide some evidence that the p.Ser166Phe variant may impact protein function (Liu 2012). However, these types of assays may not accurately represent biological function. This variant has been identified in 2/111618 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs727504242). In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Ser166Phe variant is uncertain.
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).

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