NM_001256317.3(TMPRSS3):c.647G>A (p.Arg216His) AND not provided

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jun 11, 2024
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:: RCV001558227.4

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.647G>A (p.Arg216His)]

NM_001256317.3(TMPRSS3):c.647G>A (p.Arg216His)

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.647G>A (p.Arg216His)

HGVS:

NC_000021.9:g.42383168C>T
NG_011629.2:g.17924G>A
NM_001256317.3:c.647G>AMANE SELECT
NM_024022.4:c.647G>A
NM_032404.3:c.266G>A
NM_032405.2:c.647G>A
NP_001243246.1:p.Arg216His
NP_076927.1:p.Arg216His
NP_115780.1:p.Arg89His
NP_115781.1:p.Arg216His
NC_000021.8:g.43803277C>T
NM_024022.2:c.647G>A
c.647G>A

Protein change:

R216H

Links:

dbSNP: rs137853000

NCBI 1000 Genomes Browser:

rs137853000

Molecular consequence:

NM_001256317.3:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024022.4:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032404.3:c.266G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032405.2:c.647G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001780128	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Jun 11, 2024)	germline	clinical testing	Citation Link,
SCV004297397	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 26445815, 17551081, 34440452, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001780128

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Jun 11, 2024)

germline

clinical testing

Citation Link,

SCV004297397

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 12, 2023)

germline

clinical testing

PubMed (4)
[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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Characterising the spectrum of autosomal recessive hereditary hearing loss in Iran.

Sloan-Heggen CM, Babanejad M, Beheshtian M, Simpson AC, Booth KT, Ardalani F, Frees KL, Mohseni M, Mozafari R, Mehrjoo Z, Jamali L, Vaziri S, Akhtarkhavari T, Bazazzadegan N, Nikzat N, Arzhangi S, Sabbagh F, Otukesh H, Seifati SM, Khodaei H, Taghdiri M, Meyer NC, et al.

J Med Genet. 2015 Dec;52(12):823-9. doi: 10.1136/jmedgenet-2015-103389. Epub 2015 Oct 7.

PubMed [citation]

PMID:: 26445815
PMCID:: PMC4733363

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

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV001780128.2

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 26445815)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004297397.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 216 of the TMPRSS3 protein (p.Arg216His). This variant is present in population databases (rs137853000, gnomAD 0.01%). This missense change has been observed in individual(s) with deafness (PMID: 26445815). ClinVar contains an entry for this variant (Variation ID: 46127). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TMPRSS3 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg216 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17551081, 34440452). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Oct 8, 2024

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