ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.574G>A (p.Glu192Lys) (rs199476315)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000208146 SCV000264261 pathogenic Primary familial hypertrophic cardiomyopathy 2015-11-05 criteria provided, single submitter clinical testing
GeneDx RCV000024578 SCV000209318 pathogenic not provided 2018-12-03 criteria provided, single submitter clinical testing The E192K pathogenic variant in the TPM1 gene has been reported in multiple individuals with HCM and one individual with LVNC (Ho et al., 2009; Deva et al., 2013; Probst et al., 2011; Mango et al., 2016). Mango et al. (2016) observed E192K co-segregating with HCM in four relatives, who also had signs of Brugada syndrome on EKG. It was also reported in four individuals who were either diagnosed with HCM or referred for HCM testing (Kapplinger et al., 2014). Additionally, E192K has been identified independently and/or in conjunction with additional cardiogenetic variants in over 15 individuals referred for genetic testing at GeneDx for cardiomyopathy. The E192K variant has not been observed in large population cohorts (Lek et al., 2016). Finally, E192K results in 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, and this substitution occurs at a position that is conserved across species.
Invitae RCV000526765 SCV000623807 pathogenic Hypertrophic cardiomyopathy 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 192 of the TPM1 protein (p.Glu192Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature co-segregating with disease in a family affected with hypertrophic cardiomyopathy (HCM) (PMID: 26960954). It has also been reported in multiple individuals affected with HCM or with suspected HCM (PMID: 23771913, 27639548, 18409188, 20031602, 24510615) and in one individual affected with left-ventricular non-compaction (LVNC) (PMID: 21551322). ClinVar contains an entry for this variant (Variation ID: 31882). A computational algorithm designed to assess the pathogenicity of variants in TPM1 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000526765 SCV000060282 likely pathogenic Hypertrophic cardiomyopathy 2015-10-29 criteria provided, single submitter clinical testing 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.
Leiden Muscular Dystrophy (TPM1) RCV000024578 SCV000045887 not provided not provided 2012-04-15 no assertion provided curation
OMIM RCV000054795 SCV000083040 pathogenic Left ventricular noncompaction 9 2011-08-01 no assertion criteria provided literature only
Phosphorus, Inc. RCV000578109 SCV000679817 pathogenic Familial hypertrophic cardiomyopathy 3 2017-08-01 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000024578 SCV000280539 likely pathogenic not provided 2016-08-05 no assertion criteria provided provider interpretation 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).

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