NM_001256317.3(TMPRSS3):c.916G>A (p.Ala306Thr) AND Autosomal recessive nonsyndromic hearing loss 8

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 1, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000779355.7

Allele description

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:: Autosomal recessive nonsyndromic hearing loss 8
Synonyms:: NEUROSENSORY NONSYNDROMIC RECESSIVE DEAFNESS 8; Deafness, autosomal recessive 8; Deafness, autosomal recessive 10
Identifiers:: MONDO: MONDO:0010987; MedGen: C1832827; Orphanet: 90636; OMIM: 601072

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000915954	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Sep 6, 2018)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 28246597, 21786053, 23958653, 24526180, 17551081 Citation Link,
SCV001745849	Center of Genomic medicine, Geneva, University Hospital of Geneva	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 10, 2021)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001792228	Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic	germline	research	PubMed (2) [See all records that cite these PMIDs] 30311386, 34599368
SCV002572748	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23958653, 24526180, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	4	not provided	not provided	4	yes	research, clinical testing

Citations

PubMed

Novel Mutations and Mutation Combinations of TMPRSS3 Cause Various Phenotypes in One Chinese Family with Autosomal Recessive Hearing Impairment.

Gao X, Yuan YY, Wang GJ, Xu JC, Su Y, Lin X, Dai P.

Biomed Res Int. 2017;2017:4707315. doi: 10.1155/2017/4707315. Epub 2017 Jan 29.

PubMed [citation]

PMID:: 28246597
PMCID:: PMC5303592

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 Illumina Laboratory Services, Illumina, SCV000915954.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Across a selection of the available literature, the TMPRSS3 c.916G>A (p.Ala306Thr) variant has been identified in a homozygous state in two siblings and in a compound heterozygous state in 15 individuals from nine families with autosomal recessive hearing loss (Elbracht et al. 2007; Weegerink et al. 2011; Lee et al. 2013; Chung et al. 2014; Gao et al. 2017). The variant was also found in a heterozygous state in at least three family members with normal hearing. Co-segregation of the variant with disease was demonstrated in at least one family (Gao et al. 2017), and has been suggested to be a founder variant in the Korean population, as two families with the variant were found to share the same haplotype (Chung et al. 2014). The p.Ala306Thr variant was absent from 1770 control chromosomes and is reported at a frequency of 0.00104 in the East Asian population of the Exome Aggregation Consortium. An in vitro yeast-based protease assay showed that the p.Ala306Thr variant-containing protein exhibited significantly reduced protease activity compared to the wild type protein as well as proteins containing other missense variants, consistent with the location of the variant near the Asp304 active site (Chung et al. 2014). Based on the collective evidence, the p.Ala306Thr variant is classified as pathogenic for autosomal recessive nonsyndromic hearing loss. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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		not provided	not provided	not provided	not provided

From Center of Genomic medicine, Geneva, University Hospital of Geneva, SCV001745849.1

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

Description

This variant was identified in compound heterozygosity with another variant in the same gene in a male patient with prelingual bilateral severe hearing loss

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

From Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital, SCV001792228.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	yes	research	PubMed (2)
2	not provided	1	not provided	yes	research	PubMed (2)
3	not provided	1	not provided	yes	research	PubMed (2)

Description

in compound heterozygosis with the c.1276G>A variant in three siblings with bilateral non-syndromic sensorineural postlingual progressive hearing loss; 7 normal hearing heterozygous of either variant, 2 normal hearing w/o variants (familial)

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

From 3billion, SCV002572748.1

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

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.85; 3Cnet: 0.83). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000046131). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 23958653 , 24526180). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Jun 23, 2024

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