Description
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).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | not provided | not provided | not provided | not provided | | 10 | not provided | not provided | not provided |
