NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr) AND Rare genetic deafness

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 12, 2019
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:: RCV000039368.7

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)]

NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

21q22.3

Genomic location:

Preferred name:

NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr)

HGVS:

NC_000021.9:g.42382101C>T
NG_011629.2:g.18991G>A
NM_001256317.3:c.916G>AMANE SELECT
NM_024022.4:c.916G>A
NM_032404.3:c.535G>A
NM_032405.2:c.916G>A
NP_001243246.1:p.Ala306Thr
NP_076927.1:p.Ala306Thr
NP_115780.1:p.Ala179Thr
NP_115781.1:p.Ala306Thr
NC_000021.8:g.43802210C>T
NM_024022.2:c.916G>A
NM_032405.1:c.916G>A
c.916G>A
p.(Ala306Thr)

Protein change:

A179T

Links:

dbSNP: rs181949335

NCBI 1000 Genomes Browser:

rs181949335

Molecular consequence:

NM_001256317.3:c.916G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024022.4:c.916G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032404.3:c.535G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032405.2:c.916G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Rare genetic deafness
Identifiers:: MedGen: C5680250; Orphanet: 96210

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000063052	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 12, 2019)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 17551081, 21786053, 23208854, 23958653, 24526180, 28246597, 28695016, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000063052

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 12, 2019)

germline

clinical testing

PubMed (8)
[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	unknown	3	3	not provided	not provided	not provided	clinical testing

Citations

PubMed

Autosomal recessive postlingual hearing loss (DFNB8): compound heterozygosity for two novel TMPRSS3 mutations in German siblings.

Elbracht M, Senderek J, Eggermann T, Thürmer C, Park J, Westhofen M, Zerres K.

J Med Genet. 2007 Jun;44(6):e81.

PubMed [citation]

PMID:: 17551081
PMCID:: PMC2752172

Genotype-phenotype correlation in DFNB8/10 families with TMPRSS3 mutations.

Weegerink NJ, Schraders M, Oostrik J, Huygen PL, Strom TM, Granneman S, Pennings RJ, Venselaar H, Hoefsloot LH, Elting M, Cremers CW, Admiraal RJ, Kremer H, Kunst HP.

J Assoc Res Otolaryngol. 2011 Dec;12(6):753-66. doi: 10.1007/s10162-011-0282-3. Epub 2011 Jul 23.

PubMed [citation]

PMID:: 21786053
PMCID:: PMC3214237

See all PubMed Citations (8)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000063052.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (8)

Description

The p.Ala306Thr variant in TMPRSS3 has been reported in >10 individuals with autosomal recessive hearing loss and segregated in >10 affected relatives in >5 families (Elbracht 2007, Weegerink 2011, Schrauwen 2012, Lee 2013, Chung 2014, Gao 2017a, Gao 2017b). All affected individuals were either homozygous or compound heterozygous. This variant has also been identified in 0.06% (12/19954) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Chung 2014). Computational prediction tools and conservation analysis also support a functional impact. In summary, the p.Ala306Thr variant meets criteria to be classified as pathogenic for autosomal recessive nonsyndromic hearing loss. ACMG/AMP criteria applied: PM3_VeryStrong, PP1_Strong, PM2_Supporting, PP3, PS3_Supporting.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		3	not provided	3	not provided

Last Updated: Apr 15, 2024

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