ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); 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: 27532257, 12858563, 12860912, 25241052, 23700264, 21415410, 24510615, 20031602, 21551322, 26960954, 27639548, 21310275, 16365313, 25524337, 18409188, 23771913, 27376658, 25611685, 23396983, 24033266, 31006259, 34319370, 28193612, 35176663, 33297573, 34540771, 28615295)

The p.E192K pathogenic mutation (also known as c.574G>A), located in coding exon 6 of the TPM1 gene, results from a G to A substitution at nucleotide position 574. The glutamic acid at codon 192 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in numerous individuals with hypertrophic cardiomyopathy (HCM) and was shown to co-segregate with disease in one family (Deva DP et al. Radiology. 2013;269:68-76; Coppini R et al. J. Am. Coll. Cardiol. 2014;64:2589-2600; Kapplinger JD et al. J Cardiovasc Transl Res. 2014;7:347-61; Lopes LR et al. Heart. 2015;101:294-301; Mango R et al. Circ. J. 2016;80:938-49; Ross SB et al. Circ Cardiovasc Genet. 2017;10(3):e001671; Walsh R et al. Genet. Med. 2017;19:192-203). This variant has also been detected in one patient with left ventricular noncompaction (LVNC) (Probst S et al. Circ Cardiovasc Genet. 2011;4:367-74). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established, although it has been suggested that that HCM is caused by gain of function missense variants while DCM is caused by loss of function missense variants (PMID: 31270709). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene have been associated with late-onset disease or incomplete penetrance (PMIDs: 33642254; 32882290, 32731933). (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated tropomyosin domain (DECIPHER). (I) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals or families with HCM and is the most common TPM1 pathogenic variant associated with HCM (ClinVar, PMIDs: 24510615, 27532257; 21551322, 26960954, 34638741). (SP) 1208 - Inheritance information is currently unavailable for this individual. (I) Legend: (SP) - Supporting Pathogenic, (I) – Information, (SB) – Supporting Benign

The p.Glu192Lys variant in TPM1 has been reported in more than 20 individuals wi th HCM (Van Driest 2003, Ho 2009, Probst 2011, Deva 2013, Kapplinger 2014, Coppi ni 2014, LMM unpublished data) and segregated with disease in 4 affected relativ es from 4 different families (LMM unpublished data). It is absent from large pop ulation studies. Glutamic acid (Glu) at position 192 is highly conserved in mamm als and across evolutionarily distant species and the change to Lysine (Lys) was predicted to be pathogenic using a computational tool clinically validated by o ur laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significa nce.

This TPM1 Glu192Lys has since been identified in numerous HCM cases and co-segregated in affected family members (Ho CY, et al., 2009; Probst S, et al., 2011; Deva DP, et al., 2013; Kapplinger JD, et al., 2014; Mango R, et al., 2016; ClinVar:SCV000209318, SCV000220120; https://cardiodb.org/ACGV/acgv_variant.php?id=5992). Interestingly, Mango et al., (2016) identified this variant co-segregating with HCM in 4 affected family members who also had signs of Brugada Syndrome. Furthermore, this variant is absent in population databases including the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/). Glutamic acid (Glu) at position 192 is highly conserved across distantly related species and in silico tools (SIFT, MutationTaster, PolyPhen-2) predict this variant to be disease-causing. We have identified this variant in one HCM patient with moderate asymmetric hypertrophy. There is no family history of HCM or SCD. In summary, based on its absence in the general population, observation in multiple unrelated HCM cases, strong segregation data and in silico predictions, we classify TPM1 Glu192Lys as "pathogenic".

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 192 of the TPM1 protein (p.Glu192Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) and left-ventricular non-compaction (LVNC) and HCM (PMID: 18409188, 20031602, 21551322, 23771913, 24510615, 26960954, 27639548). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31882). An algorithm developed specifically for the TPM1 gene suggests that this missense change is likely to be deleterious (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.

The TPM1 gene encodes Tropomyosin 1 which involves in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Mutations in TPM1 result in Hypertrophic cardiomyopathy with an autosomal dominant inheritance (OMIM: 115196).

p.Glu192Lys (c.574G>A) in the TPM1 gene. Seen in our center in an adult with HCM with a family history of HCM and sudden death. We re-reviewed the results August 4th, 2016. We had initially classified this as a VUS. Given the strong case data and absence in controls we now consider the variant likely pathogenic and we do feel it is appropriate for assessing risk in healthy relatives (predictive genetic testing). Seen in at least 18 presumably unrelated cases of HCM (7 published, 11 unpublished) and one case of LVNC. It has segregated with disease in at least three affected relatives. Deva et al. (2013) reported this variant in one out of 300 patients with HCM that were cared for in Toronto, Canada, who underwent analysis of unreported genes. Ancestry was not reported. Ho et al. (2009) reported this variant in one out of 40 patients with HCM that were cared for in Boston, MA, Minneapolis, MN, and Copenhagen, Denmark, who underwent analysis of at least the MYH7, MYBPC3, TNNT2, TNNI3, and TPM1 genes. Kapplinger et al. (2013) reported this variant in four out of 2,178 patients with HCM that were cared for in Mayo Clinic in Rochester, Minnesota or tested by Transgenomic Inc. Patients underwent analysis of the MYH7, MYL2, MYL3, MYBPC3, ACTC, TNNC1, TNNI3, TNNT2, and TPM1 genes. Patient specific ancestry was not reported. Fokstuen et al. (2008) reported this variant in one out of 8 patients with HCM of unreported ancestry that were cared for in University College London Hospitals, London, United Kingdom. They performed analysis of HCM associated genes including: MYH7, MYBPC3, TNNT2, TPM1, TNNI3, MYL3, MYL2, CSRP3, PLN, ACTC, TNNC1, and PRKAG2. Probst et al. (2011) reported this variant in one out of 63 LVNC cases of western European ancestry that were cared for in University Hospital Zurich, Switzerland, and the German Heart Institute Berlin, Germany, who underwent analysis of MYH7, ACTC1, TNNT2, TNNI3, MYL2, MYL3, TPM1 and MYBPC3 genes. The proband is a 55-year-old male, who presented with sudden chest pain, dyspnea, pronounced midventricular wall LVNC and increased right ventricular trabeculations. In LMM's summary report submitted to ClinVar (4/10/2014), they note that they have identified this variant in at least 11 presumably unrelated cases of HCM and 3 affected family members (unclear if they are from the same family or different families). These cases likely overlap with others, including those reported by Ho et al. In silico analysis with PolyPhen-2 predicts the variant to be benign and SIFT predicts the variant to be not tolerated. Glutamic acid at position 192 is highly conserved in mammals and across evolutionarily distant species. No other variants have been reported in association with disease at this codon. This variant lies in the troponin T binding region of alpha-tropomyosin, as do several other TPM1 variants that have been observed in patients with primary cardiomyopathies (p.Ile172Thr; p.Asp175Asn; p.Glu180Gly; p.Glu180Val; p.Leu185Arg) (Jagatheesan, 2010). It has been suggested that variants in this domain may disrupt calcium signaling and tropomyosin - troponin T binding (Wieczorek, 2008). LMM notes that a computational tool clinically validated by their laboratory predicts this variant to be pathogenic. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan, 2011). In total the variant has not been seen in ~61,476 individuals from published controls and publicly available datasets that approximate the general population. The variant was absent in 60,335 individuals in the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/), which currently includes variant calls on ~64,000 individuals of European, African, Latino and Asian descent (as of April 22nd, 2015). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population; others were enriched for common cardiovascular disease. Median coverage in ExAC is >70. The variant was not observed in the following lab control samples: 400 by Familion labs. The variant was not observed in the following published control samples: 38 in Ho (2009), 96 in Fokstuen (2008), and 427 in Kapplinger (2013), 180 in Probst (2011).