rs199476153

chr9-35685508-TCTC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4_Supporting PP3 PP5_Very_Strong

The NM_003289.4(TPM2):c.415_417del(p.Glu139del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TPM2 NM_003289.4 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 8.01

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a chain Tropomyosin beta chain (size 283) in uniprot entity TPM2_HUMAN there are 62 pathogenic changes around while only 5 benign (93%) in NM_003289.4
• PM4: Nonframeshift variant in NON repetitive region in NM_003289.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 9-35685508-TCTC-T is Pathogenic according to our data. Variant chr9-35685508-TCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 12465.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-35685508-TCTC-T is described in Lovd as [Pathogenic]. Variant chr9-35685508-TCTC-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TPM2	NM_003289.4	c.415_417del	p.Glu139del	inframe_deletion	4/9	ENST00000645482.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPM2	ENST00000645482.3	c.415_417del	p.Glu139del	inframe_deletion	4/9		NM_003289.4	A1

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:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myopathy 23 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Nov 04, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 28, 2016	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	TPM2: PS2, PM2, PS3:Moderate, PS4:Moderate -
not provided, no classification provided	literature only	TPM2 homepage - Leiden Muscular Dystrophy pages	-	- -

Arthrogryposis, distal, type 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 04, 2020

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 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). This variant is not present in population databases (ExAC no frequency). 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. -

TPM2-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 15, 2024

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

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

Other links and lift over

dbSNP: rs199476153; hg19: chr9-35685505;