NM_001256317.3(TMPRSS3):c.326G>A (p.Arg109Gln) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Jan 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000493533.12

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.326G>A (p.Arg109Gln)]

NM_001256317.3(TMPRSS3):c.326G>A (p.Arg109Gln)

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.326G>A (p.Arg109Gln)

HGVS:

NC_000021.9:g.42388523C>T
NG_011629.2:g.12569G>A
NM_001256317.3:c.326G>AMANE SELECT
NM_024022.4:c.326G>A
NM_032404.3:c.-56G>A
NM_032405.2:c.326G>A
NP_001243246.1:p.Arg109Gln
NP_076927.1:p.Arg109Gln
NP_115781.1:p.Arg109Gln
NC_000021.8:g.43808632C>T
NM_024022.2:c.326G>A

Protein change:

R109Q

Links:

dbSNP: rs139484231

NCBI 1000 Genomes Browser:

rs139484231

Molecular consequence:

NM_032404.3:c.-56G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001256317.3:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_024022.4:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_032405.2:c.326G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000231181	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Dec 10, 2014)	germline	clinical testing	Citation Link,
SCV000582645	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (May 18, 2017)	germline	clinical testing	Citation Link,
SCV002232524	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24853665, 11424922, 12920079, 28566687, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000231181

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Dec 10, 2014)

germline

clinical testing

Citation Link,

SCV000582645

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(May 18, 2017)

germline

clinical testing

Citation Link,

SCV002232524

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 29, 2024)

germline

clinical testing

PubMed (5)
[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	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic testing for sporadic hearing loss using targeted massively parallel sequencing identifies 10 novel mutations.

Gu X, Guo L, Ji H, Sun S, Chai R, Wang L, Li H.

Clin Genet. 2015 Jun;87(6):588-93. doi: 10.1111/cge.12431. Epub 2014 Aug 7.

PubMed [citation]

PMID:: 24853665

Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness.

Ben-Yosef T, Wattenhofer M, Riazuddin S, Ahmed ZM, Scott HS, Kudoh J, Shibuya K, Antonarakis SE, Bonne-Tamir B, Radhakrishna U, Naz S, Ahmed Z, Riazuddin S, Pandya A, Nance WE, Wilcox ER, Friedman TB, Morell RJ.

J Med Genet. 2001 Jun;38(6):396-400. No abstract available.

PubMed [citation]

PMID:: 11424922
PMCID:: PMC1734898

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000231181.5

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

From GeneDx, SCV000582645.3

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

Description

The R109Q variant in the TMPRSS3 gene has been reported previously in the compound heterozygous state in an individual with moderate non-syndromic hearing loss (Gu et al., 2015). The R109Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A different missense variant at this residue (R109W) has been reported in the Human Gene Mutation Database in association with non-syndromic hearing loss (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R109Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret R109Q as a likely pathogenic variant.

#	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 Invitae, SCV002232524.3

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

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 109 of the TMPRSS3 protein (p.Arg109Gln). This variant is present in population databases (rs139484231, gnomAD 0.03%). This missense change has been observed in individual(s) with sensorineural deafness (PMID: 24853665; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 197857). 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 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg109 amino acid residue in TMPRSS3. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11424922, 12920079, 28566687). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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

Last Updated: Mar 10, 2024

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