rs137853305

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1PM2PM5PP2PP3_ModeratePP5_Very_Strong

The NM_003289.4(TPM2):c.397C>T(p.Arg133Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R133P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TPM2
NM_003289.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.65

Variant links:

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

TPM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 17 ACMG points.

PM1

In a region_of_interest Disordered (size 19) in uniprot entity TPM2_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_003289.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-35685528-C-G is described in Lovd as [Likely_pathogenic].

PP2

Missense variant in the TPM2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 19 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 2.1346 (below the threshold of 3.09). Trascript score misZ: 3.2995 (above the threshold of 3.09). GenCC associations: The gene is linked to cap myopathy, typical nemaline myopathy, digitotalar dysmorphism, congenital fiber-type disproportion myopathy, childhood-onset nemaline myopathy, congenital myopathy 23, Sheldon-hall syndrome, arthrogryposis, distal, type 1A, TPM2-related myopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 9-35685529-G-A is Pathogenic according to our data. Variant chr9-35685529-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35685529-G-A is described in Lovd as [Pathogenic]. Variant chr9-35685529-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4 link	c.397C>T	p.Arg133Trp	missense_variant	Exon 4 of 9	ENST00000645482.3	NP_003280.2	P07951-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3 link	c.397C>T	p.Arg133Trp	missense_variant	Exon 4 of 9		NM_003289.4	ENSP00000496494.2		P07951-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727246

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Arthrogryposis, distal, type 1A

Pathogenic:4

Feb 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 133 of the TPM2 protein (p.Arg133Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with arthrogryposis and/or congenital myopathy (PMID: 17339586, 23678273, 24692096, 32092148). ClinVar contains an entry for this variant (Variation ID: 12463). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TPM2 protein function with a positive predictive value of 80%. This variant disrupts the p.Arg133 amino acid residue in TPM2. Other variant(s) that disrupt this residue have been observed in individuals with TPM2-related conditions (PMID: 24692096), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Oct 02, 2021

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23678273,17339586, PS1_S). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). It is not observed in the gnomAD v2.1.1 dataset (PM2).In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.788, 3Cnet: 0.871, PP3). Patient's phenotype is considered compatible with Arthrogryposis, distal, (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 06, 2019

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Suma Genomics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2Other:1

Jan 09, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TPM2 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jun 30, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies suggest a damaging effect during activation as the variant partially inhibits both calcium- and myosin-induced tropomyosin movement over the thin filament (Ochala et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); 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: 26307083, 22519952, 23401156, 18422639, 24692096, 23678273, 17339586, 17430991, 31526942, 32092148, 30199282, 31535252, 31864708, 32528171, 20457903, 35579956, 33066566, Neissi2022[Case Report]) -

Arthrogryposis

Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4,PS3,PM2,PP3 -

TPM2-related disorder

Pathogenic:1

Nov 28, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TPM2 c.397C>T variant is predicted to result in the amino acid substitution p.Arg133Trp. This variant has been reported in many unrelated individuals to be causative for TPM2-related disorders (Ochala et al. 2007. PubMed ID 17430991; Marttila et al. 2014. PubMed ID: 24692096; Beck et al. 2013. PubMed ID: 23401156; Table S4, Töpf et al. 2020. PubMed ID: 32528171; Vogt et al. 2020. PubMed ID: 32092148). Functional studies suggested that this variant leads to disrupted regulation of muscle contraction (Ochala et al. 2007. PubMed ID: 17430991). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/12463/). This variant is interpreted as pathogenic. -

Arthrogryposis, distal, type 2B4

Pathogenic:1

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;D;.;D;D;D

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.85

.;T;T;.;T;T

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

4.1

H;.;H;H;H;.

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-6.4

D;D;D;.;D;.

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D;D;D;.;D;.

Sift4G

Pathogenic

0.0

D;D;D;.;D;.

Polyphen

0.98

D;.;D;P;P;B

Vest4

0.90

MutPred

0.80

Loss of ubiquitination at K128 (P = 0.0585);Loss of ubiquitination at K128 (P = 0.0585);Loss of ubiquitination at K128 (P = 0.0585);Loss of ubiquitination at K128 (P = 0.0585);Loss of ubiquitination at K128 (P = 0.0585);Loss of ubiquitination at K128 (P = 0.0585);

MVP

0.96

MPC

2.2

ClinPred

0.99

GERP RS

-0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.53

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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