rs199476153

Variant names:

• chr9-35685508-TCTC-T
• rs199476153
• NM_003289.4:c.415_417delGAG

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_003289.4(TPM2):​c.415_417delGAG​(p.Glu139del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 8.01
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• TPM2-related myopathy

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• arthrogryposis, distal, type 1A

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• congenital myopathy 23

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• cap myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• childhood-onset nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• congenital fiber-type disproportion myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• digitotalar dysmorphism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Sheldon-hall syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• typical nemaline myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 13 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, 7 uncertain in NM_003289.4
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_003289.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 9-35685508-TCTC-T is Pathogenic according to our data. Variant chr9-35685508-TCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 12465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPM2	NM_003289.4	c.415_417delGAG	p.Glu139del	conservative_inframe_deletion	Exon 4 of 9	ENST00000645482.3	NP_003280.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.415_417delGAG	p.Glu139del	conservative_inframe_deletion	Exon 4 of 9		NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myopathy 23 Pathogenic:5

Mar 06, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM1, PM2, PM4, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 12465). This variant has been previously reported as causative for congenital myopathy (PMID:24507666). -

May 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 28, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 07, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TPM2 c.415_417delGAG (p.Glu139del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 251480 control chromosomes. c.415_417delGAG has been reported in the literature in multiple individuals affected with Nemaline Myopathy 4 (Cap myopathy) (example, Lehtokari_2007, Clarke_2009, Tasca_2013, Citirak_2014). Some of the ascertained reports indicated a de-novo origin and at-least once instance of somatic mosaicism resulting in a milder presentation has been reported (example, Tasca_2013). These data indicate that the variant is likely to be associated with disease. At least two publications report experimental evidence that the mutant protein incorporates into sarcomeric structures, where it likely imposes a dominant-negative effect to cause muscle weakness (example, Clarke_2009) and increased myofibrillar calcium sensitivity consistent with a gain of function mechanism (example, Marston_2013). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 04, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

TPM2 homepage - Leiden Muscular Dystrophy pages

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate -

Arthrogryposis, distal, type 1A Pathogenic:1

Mar 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this in-frame deletion causes increased calcium sensitivity and inhibits myosin binding (PMID: 23886664, 25978979). This variant, c.415_417del, results in the deletion of 1 amino acid of the TPM2 protein (p.Glu139del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple unrelated individuals affected with autosomal dominant cap myopathy and nemaline myopathy (PMID: 17434307, 23015096, 24692096, 25127990), including several affected individuals where it arose de novo (PMID: 19345583, 24507666). ClinVar contains an entry for this variant (Variation ID: 12465). -

TPM2-related disorder Pathogenic:1

Feb 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TPM2 c.415_417delGAG variant is predicted to result in an in-frame deletion (p.Glu139del). This variant was reported in numerous individuals with nemaline myopathy or CAP myopathy (Lehtokari et al. 2007. PubMed ID: 17434307; Marttila et al. 2014. PubMed ID: 24692096; Table S1, Westra et al. 2019. PubMed ID: 31127727; Supplementary data, Gonzalez-Quereda et al. 2020. PubMed ID: 32403337). Functional studies showed that this variant impacts normal protein function (Marttila et al. 2012. PubMed ID: 22084935; Marston et al. 2013. PubMed ID: 23886664; Borovikov et al. 2015. PubMed ID: 25978979). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0
Mutation Taster		=52/48	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199476153; hg19: chr9-35685505;