NM_001256317.3(TMPRSS3):c.208del (p.His70fs) AND Nonsyndromic genetic hearing loss

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 5, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003993831.1

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.208del (p.His70fs)]

NM_001256317.3(TMPRSS3):c.208del (p.His70fs)

Gene:

TMPRSS3:transmembrane serine protease 3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_001256317.3(TMPRSS3):c.208del (p.His70fs)

HGVS:

NC_000021.8:g.43809152del
NC_000021.9:g.42389044del
NG_011629.2:g.12049del
NM_001256317.3:c.208delMANE SELECT
NM_024022.4:c.208del
NM_032404.3:c.-174del
NM_032405.2:c.208del
NP_001243246.1:p.His70fs
NP_076927.1:p.His70fs
NP_115781.1:p.His70fs
NC_000021.8:g.43809152del
NC_000021.8:g.43809152delG
NC_000021.8:g.43809153del
NC_000021.9:g.42389043delG
NM_001256317.1:c.208delC
NM_001256317.3:c.208del
NM_001256317.3:c.208delCMANE SELECT
NM_024022.2:c.208del
NM_024022.2:c.208delC
NM_024022.3:c.208delC
p.His70ThrfsX19

Protein change:

H70fs

Links:

OMIM: 605511.0006; dbSNP: rs727503493

NCBI 1000 Genomes Browser:

rs727503493

Molecular consequence:

NM_032404.3:c.-174del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001256317.3:c.208del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_024022.4:c.208del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_032405.2:c.208del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Nonsyndromic genetic hearing loss
Synonyms:: Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:: MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004812871	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 21534946, 26036852, 28566687, 29293505, 30242206, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004812871

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2024)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel TMPRSS3 variants in Pakistani families with autosomal recessive non-syndromic hearing impairment.

Lee K, Khan S, Islam A, Ansar M, Andrade PB, Kim S, Santos-Cortez RL, Ahmad W, Leal SM.

Clin Genet. 2012 Jul;82(1):56-63. doi: 10.1111/j.1399-0004.2011.01695.x. Epub 2011 May 25.

PubMed [citation]

PMID:: 21534946
PMCID:: PMC3374056

TMPRSS3 mutations in autosomal recessive nonsyndromic hearing loss.

Battelino S, Klancar G, Kovac J, Battelino T, Trebusak Podkrajsek K.

Eur Arch Otorhinolaryngol. 2016 May;273(5):1151-4. doi: 10.1007/s00405-015-3671-0. Epub 2015 Jun 3.

PubMed [citation]

PMID:: 26036852

See all PubMed Citations (6)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV004812871.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change in TMPRSS3 is a frameshift variant predicted to cause a premature stop codon, p.(His70Thrfs*19), in biologically relevant exon 4/13 leading to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism. The highest population minor allele frequency in the population database gnomAD v4.0 is 0.1% (1,202/1,180,022 alleles) in the European (non-Finnish) population. The variant has been reported to segregate with hearing loss in affected family members from two unrelated families (PMID: 21534946, 26036852). This variant has been detected in multiple individuals with hearing loss. Of those individuals, at least two individuals were homozygous while the majority of the reported individuals were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (PMID: 29293505, 30242206, 26036852, 28566687). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PP1_Strong, PVS1

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 30, 2024

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