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

gnomAD frequency: 0.00001  dbSNP: rs199476316

Total submissions: 10

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	2020-04-14	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 (https://gnomad.broadinstitute.org/). 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	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