rs199476316

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_001018005.2(TPM1):c.644C>T(p.Ser215Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,842 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S215S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TPM1
NM_001018005.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.81

Variant links:

Genes affected

TPM1 (HGNC:12010): (tropomyosin 1) This gene is a member of the tropomyosin family of highly conserved, widely distributed actin-binding proteins involved in the contractile system of striated and smooth muscles and the cytoskeleton of non-muscle cells. Tropomyosin is composed of two alpha-helical chains arranged as a coiled-coil. It is polymerized end to end along the two grooves of actin filaments and provides stability to the filaments. The encoded protein is one type of alpha helical chain that forms the predominant tropomyosin of striated muscle, where it also functions in association with the troponin complex to regulate the calcium-dependent interaction of actin and myosin during muscle contraction. In smooth muscle and non-muscle cells, alternatively spliced transcript variants encoding a range of isoforms have been described. Mutations in this gene are associated with type 3 familial hypertrophic cardiomyopathy and dilated cardiomyopathy 1Y. [provided by RefSeq, Jun 2022]

TPM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_001018005.2

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, TPM1

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 15-63062219-C-T is Pathogenic according to our data. Variant chr15-63062219-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-63062219-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM1	NM_001018005.2 linkuse as main transcript	c.644C>T	p.Ser215Leu	missense_variant	7/10	ENST00000403994.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM1	ENST00000403994.9 linkuse as main transcript	c.644C>T	p.Ser215Leu	missense_variant	7/10	1	NM_001018005.2	A1	P09493-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251270

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461748

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2023	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) -
Likely pathogenic, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 17, 2016	- -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (TPM1)	Apr 15, 2012	- -

Cardiomyopathy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Aug 01, 2017	- -
Likely pathogenic, no assertion criteria provided	literature only	Evolutionary and Medical Genetics Laboratory, Centre for Cellular and Molecular Biology	-	- -

Hypertrophic cardiomyopathy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2020	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 (https://gnomad.broadinstitute.org/). 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. -

Dilated cardiomyopathy 1Y

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

KTest Genetics, KTest

- -

Primary familial hypertrophic cardiomyopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Sep 28, 2015

- -

Cardiovascular phenotype

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 07, 2020

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

CardioboostCm

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.88

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

M;M;M;.;M;M;M;M;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.4

D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D

REVEL

Pathogenic

0.87

Sift

Benign

0.047

D;D;D;D;D;D;D;.;.;D;D;.;D;D;D;D

Sift4G

Benign

0.13

T;T;T;T;T;T;T;.;.;T;T;.;T;T;T;T

Polyphen

0.91, 0.99, 0.74, 1.0

.;.;P;D;.;.;.;P;.;.;.;.;.;D;.;.

Vest4

0.90

MutPred

0.67

.;.;.;Loss of phosphorylation at S257 (P = 0.0094);.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.97

MPC

2.2

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

2.7

Varity_R

0.49

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over