ClinVar Miner

Submissions for variant NM_001018005.2(TPM1):c.644C>T (p.Ser215Leu) (rs199476316)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000168063 SCV000060002 likely pathogenic Hypertrophic cardiomyopathy 2020-04-14 criteria provided, single submitter clinical testing The p.Ser215Leu variant in TPM1 has been reported in at least 7 individuals with HCM and segregated with disease in 6 individuals from 3 families (Morita 2008 PMID: 18403758, Rangaraju 2012 PMID: 23204897, Selvi Rani 2015 PMID: 25607779, Cecconi 2016 PMID: 27600940, Walsh 2017 PMID: 27532257, Viswanathan 2017 PMID: 29121657, Bales 2016 PMID: 26936621). In at three families with early onset disease, this variant was identified in conjunction with a second pathogenic variant associated to cardiomyopathy, and one individual had cardiomyopathy while only harboring the second variant and not the p.Ser215Leu variant. This variant has also been reported in ClinVar (Variation ID 31883) and has been idenitified in 1/113564 of European chromosomes by gnomAD ( Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant impacts protein function (Gupte 2015 PMID: 25548289); however, these types of assays may not accurately represent biological function. 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 hypertrophic cardiomyopathy. ACMG/AMP Criteria applied: PM2, PS4_Moderate, PP3, PS3_Supporting, PP1_Moderate.
Blueprint Genetics RCV000143959 SCV000188840 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-09-28 criteria provided, single submitter clinical testing
GeneDx RCV000024579 SCV000209323 likely pathogenic not provided 2016-12-19 criteria provided, single submitter clinical testing The S215L likely pathogenic variant in the TPM1 gene has been previously reported in multiple individuals in association with HCM (Morita et al., 2008; Rangaraju et al., 2012; Selvi Rani et al., 2015; Bales et al., 2016; Cecconi et al., 2016). Morita et al. (2008) first reported this variant in an individual diagnosed with HCM before the age of 15 years and who had a family history of cardiomyopathy, although segregation studies were not reported. It has also been reported in at least two unrelated South Indian individuals diagnosed with HCM (Rangaraju et al., 2012; Selvi Rani et al., 2015); however, these individuals harbored additional cardiogenetic variants and segregation studies were non-informative as S215L co-segregated with other variants in relatives with HCM or borderline echocardiographic findings (Selvi Rani et al., 2015). Bales et al. (2016) identified S215L in a 4-year-old male diagnosed with HCM, who harbored two variants in the MYBPC3 gene and a variant in the TNNT3 gene; however, S215L was not found in his affected 1-year-old sister who harbored one of the two familial variants in the MYBPC3 gene. Finally, this variant was identified in at least one individual from a cohort of Italian patients with HCM (Cecconi et al., 2016), and has been observed both independently, and in conjunction with additional cardiogenetic variants in multiple individuals referred for HCM genetic testing at GeneDx, but informative segregation data is not available for any of these cases.The S215L variant is classified in ClinVar as a variant of uncertain significance by one clinical laboratory (ClinVar SCV000060002.4; Landrum et al., 2016), and reported as a likely pathogenic variant by two other clinical laboratories (ClinVar SCV000188840.2, SCV000218717.2; Landrum et al., 2016). The S215L variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, the S215L 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. Additionally, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, in vitro functional studies by Gupte et al. (2015) demonstrated that S215L causes significantly reduced actin binding and increased calcium sensitivity, thus affecting the contractile properties of the tropomyosin protein.Therefore, this variant is a strong candidate for a pathogenic variant, however the possibility that it is a benign variant cannot be excluded.
Invitae RCV000168063 SCV000218717 pathogenic Hypertrophic cardiomyopathy 2019-06-28 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 215 of the TPM1 protein (p.Ser215Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs199476316, ExAC 0.002%). This variant has been reported in individuals affected with hypertrophic cardiomyopathy (HCM) and to segregate with the disease in two affected families (PMID: 18403758, 23204897, 25607779, 27600940). ClinVar contains an entry for this variant (Variation ID: 31883). Experimental studies have shown that this missense change alters TPM1 protein hydrophobicity, reducing its affinity for actin (PMID: 25548289, 23700264). In summary, this rare sequence change, has been reported in multiple individuals with hypertrophic cardiomyopathy, has been shown to segregate with disease and has been shown to cause a deleterious effect on protein function. For these reasons it has been classified as Pathogenic.
Ambry Genetics RCV000617620 SCV000740012 likely pathogenic Cardiovascular phenotype 2018-10-09 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000144848 SCV000901961 likely pathogenic Cardiomyopathy 2017-08-01 criteria provided, single submitter clinical testing
Leiden Muscular Dystrophy (TPM1) RCV000024579 SCV000045888 not provided not provided 2012-04-15 no assertion provided curation
Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology RCV000144848 SCV000191868 probable-pathogenic Cardiomyopathy no assertion criteria provided not provided Converted during submission to Likely pathogenic.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000024579 SCV000924968 likely pathogenic not provided 2016-08-17 no assertion criteria provided provider interpretation

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