NM_001256317.3(TMPRSS3):c.413C>A (p.Ala138Glu) AND Autosomal recessive nonsyndromic hearing loss 8

Germline classification:: Pathogenic/Likely pathogenic (13 submissions)
Last evaluated:: Dec 1, 2023
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:: RCV000454169.23

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.413C>A (p.Ala138Glu)]

NM_001256317.3(TMPRSS3):c.413C>A (p.Ala138Glu)

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.413C>A (p.Ala138Glu)

HGVS:

NC_000021.9:g.42388436G>T
NG_011629.2:g.12656C>A
NM_001256317.3:c.413C>AMANE SELECT
NM_024022.4:c.413C>A
NM_032404.3:c.32C>A
NM_032405.2:c.413C>A
NP_001243246.1:p.Ala138Glu
NP_076927.1:p.Ala138Glu
NP_115780.1:p.Ala11Glu
NP_115781.1:p.Ala138Glu
NC_000021.8:g.43808545G>T
NM_001256317.3:c.413C>A
NM_024022.2:c.413C>A
NM_024022.3:c.413C>A
c.413C>A

Protein change:

A11E

Links:

dbSNP: rs147231991

NCBI 1000 Genomes Browser:

rs147231991

Molecular consequence:

NM_001256317.3:c.413C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024022.4:c.413C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032404.3:c.32C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032405.2:c.413C>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Decreased function

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
SCV000436174	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Mar 20, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 21786053, 22975204, 16283880 Citation Link,
SCV000538067	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001338634	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Apr 7, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22975204, 16283880, 21786053 Citation Link,
SCV001760469	Genomics England Pilot Project, Genomics England	criteria provided, single submitter (ACGS Guidelines, 2016)	Likely pathogenic	germline	clinical testing	Citation Link,
SCV001792230	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
SCV001950041	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 11, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002020239	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002569141	Genetics Laboratory, Department of Biology, Semnan University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 1, 2018)	inherited	case-control	PubMed (1) [See all records that cite this PMID]
SCV002581717	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002756434	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002767250	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16283880, 21786053, 22975204, 30242206, 25741868
SCV002785492	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 27, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004183412	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 29, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	3	not provided	not provided	1	yes	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
Semnan	inherited	no	1	not provided	not provided	not provided	not provided	case-control

Citations

PubMed

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss.

Batissoco AC, Pedroso-Campos V, Pardono E, Sampaio-Silva J, Sonoda CY, Vieira-Silva GA, da Silva de Oliveira Longati EU, Mariano D, Hoshino ACH, Tsuji RK, Jesus-Santos R, Abath-Neto O, Bento RF, Oiticica J, Lezirovitz K.

Hum Genet. 2022 Apr;141(3-4):519-538. doi: 10.1007/s00439-021-02372-2. Epub 2021 Oct 1.

PubMed [citation]

PMID:: 34599368

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000436174.3

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

Description

The TMPRSS3 c.413C>A (p.Ala138Glu) variant was identified in a total of 14 individuals with an autosomal recessive form of hearing loss, including in two homozygotes from one family and in a total of 12 compound heterozygotes from seven unrelated families. The variant was also found in a heterozygous state in three unaffected parents (Hutchin et al. 2005; Weegerink et al. 2011; Eppsteiner et al. 2012). The p.Ala138Glu variant was absent from 165 controls, but is reported at a frequency of 0.00121 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Ala138Glu 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 Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538067.1

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

Description

The c. 413C>A (p. Ala138Glu) missense variant in the TMPRSS3 gene has previously been reported as homozygous in two siblings who were affected with autosomal recessive non-syndromic hearing loss [Hutchin T et al., (2005)]. Additionally, this variant has been seen in trans with a known pathogenic variant (Ala306Thr) and also co-segregated with disease in multiple affected family members in several families [Weegerink NJ et al., (2011)]. The prevalence of this variant in affected individuals is significantly increased compared with the prevalence in controls. The frequency of this variant in the three control population databases (Exome Sequencing Project [ESP], 1000 Genomes, and ExAC) is lower than the disease-allele frequency, and no homozygotes for this variant are observed in the population databases. Several computational algorithms predict a deleterious effect of this variant on the protein. Finally, reputable clinical sources have classified this variant as either Likely Pathogenic or Pathogenic. Therefore, this collective evidence supports the Likely Pathogenic classification of the c.413C>A (p. Ala138Glu) variant in the TMPRSS3 gene for Non-syndromic hearing loss (DFNB8/10). We have confirmed this finding in our laboratory using Sanger sequencing.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001338634.1

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

Description

Variant summary: TMPRSS3 c.413C>A (p.Ala138Glu) results in a non-conservative amino acid change located in the SRCR domain (IPR001190) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 251450 control chromosomes. c.413C>A has been reported in the literature in multiple individuals affected with Deafness, autosomal recessive 8 (examples- Hutchin_2005, Weegerink_2011, Eppsteiner_2012), and has been shown to segregate with disease in affected family members. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other ClinVar submitters have cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	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 Genomics England Pilot Project, Genomics England, SCV001760469.1

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

#	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

From Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital, SCV001792230.1

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

Description

in compound heterozygosis with the c.346G>A variant in a subject with non-syndromic sensorineural postlingual progressive hearing loss (sporadic)

#	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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV001950041.1

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

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

From Revvity Omics, Revvity, SCV002020239.3

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

#	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 Genetics Laboratory, Department of Biology, Semnan University, SCV002569141.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Semnan	1	not provided	not provided	case-control	PubMed (1)

Description

The identified mutation leads to the substitution of Alanine 138 to Glutamic acid (A138E) in the TMPRSS3 protein. Hence, this substitution alters the amino acid sequence and leads to abnormal protein function.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	no	not provided	not provided	not provided		1	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002581717.1

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

#	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		1	not provided	not provided	not provided

From The Shared Resource Centre "Genome", Research Centre for Medical Genetics, SCV002756434.1

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

#	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		1	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002767250.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive deafness 8/10 (MIM#601072). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glutamic acid. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (277 heterozygotes, 0 homozygotes). (SP) 0309 - Alternative amino acid changes at the same position have been observed in gnomAD (highest allele count: p.(Ala138Thr) - v2: 165 heterozygotes, 0 homozygotes; v3: 78 heterozygotes, 1 homozygote). (I) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (I) 0600 - Variant is located in the annotated scavenger receptor cysteine-rich domain (NCBI, PDB). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple unrelated individuals with hearing loss (PMID: 16283880, 21786053, 22975204, 30242206), and as pathogenic in ClinVar and the Deafness Variation Database. (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated with disease in at least two families with autosomal recessive non-syndromic hearing impairment (PMID: 21786053). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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

From Fulgent Genetics, Fulgent Genetics, SCV002785492.1

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

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

From Baylor Genetics, SCV004183412.1

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

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

Last Updated: Sep 29, 2024

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