ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs199476316
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000168063 SCV000060002 likely pathogenic Hypertrophic cardiomyopathy 2020-11-02 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 least 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 by other clinical laboratories in ClinVar (Variation ID 31883) and has also been identified in 0.0009% (1/113564) of European chromosomes by gnomAD ( In vitro functional studies provide some evidence that this variant impacts protein function (Gupte 2015 PMID: 25548289); and computational prediction tools and conservation analyses suggest that this variant may impact the protein. 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_supporting, 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 2023-04-12 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); Published in vitro functional studies demonstrated that p.(S215L) caused significantly reduced actin binding and increased calcium sensitivity, thus affecting the contractile properties of the tropomyosin protein (Gupte et al., 2015); 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: 18403758, 23204897, 23700264, 26936621, 27600940, 25607779, 27532257, 29121657, 25548289, 31737537, 33673806, 34011823, 36896133, 36158814)
Invitae RCV000168063 SCV000218717 pathogenic Hypertrophic cardiomyopathy 2024-01-16 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 215 of the TPM1 protein (p.Ser215Leu). This variant is present in population databases (rs199476316, gnomAD 0.0009%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (HCM) (PMID: 18403758, 23204897, 25607779, 27600940). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31883). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TPM1 function (PMID: 23700264, 25548289). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000617620 SCV000740012 pathogenic Cardiovascular phenotype 2020-05-07 criteria provided, single submitter clinical testing The p.S215L pathogenic mutation (also known as c.644C>T), located in coding exon 7 of the TPM1 gene, results from a C to T substitution at nucleotide position 644. The serine at codon 215 is replaced by leucine, an amino acid with dissimilar properties. This variant has been reported in multiple individuals with hypertrophic cardiomyopathy in the heterozygous and compound heterozygous state, and has been found to co-segregate with disease (Morita H et al. N. Engl. J. Med. 2008;358:1899-908, Rangaraju A et al. Exp Clin. Cardiol. 2012;17:26-9, Selvi Rani D et al. DNA Cell Biol. 2015;34:350-9, Bales ND et al. Pediatr. Cardiol. 2016;37:845-51). The patients who harbored this variant in the compound heterozygous state were noted to be more severely affected (Selvi Rani D et al. DNA Cell Biol. 2015;34:350-9). An in vitro functional study showed close to a two-fold decrease in tropomyosin binding affinity for actin with hypersensitivity to calcium (Gupte TM et al. J. Biol. Chem. 2015;290:7003-15). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000144848 SCV000901961 likely pathogenic Cardiomyopathy 2017-08-01 criteria provided, single submitter clinical testing
KTest Genetics, KTest RCV001594373 SCV001499979 pathogenic Dilated cardiomyopathy 1Y 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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