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NM_001256317.3(TMPRSS3):c.1340T>C (p.Met447Thr) AND Rare genetic deafness

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Oct 24, 2015
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:
RCV000039341.6

Allele description [Variation Report for NM_001256317.3(TMPRSS3):c.1340T>C (p.Met447Thr)]

NM_001256317.3(TMPRSS3):c.1340T>C (p.Met447Thr)

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.1340T>C (p.Met447Thr)
HGVS:
  • NC_000021.9:g.42375720A>G
  • NG_011629.2:g.25372T>C
  • NM_001256317.3:c.1340T>CMANE SELECT
  • NM_024022.4:c.1343T>C
  • NM_032404.3:c.962T>C
  • NP_001243246.1:p.Met447Thr
  • NP_076927.1:p.Met448Thr
  • NP_115780.1:p.Met321Thr
  • NC_000021.8:g.43795829A>G
  • NM_024022.2:c.1343T>C
  • c.1343T>C
Protein change:
M321T
Links:
dbSNP: rs201018751
NCBI 1000 Genomes Browser:
rs201018751
Molecular consequence:
  • NM_001256317.3:c.1340T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024022.4:c.1343T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_032404.3:c.962T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000063025Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Likely pathogenic
(Oct 24, 2015)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided42not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000063025.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (1)

Description

The p.Met448Thr variant in TMPRSS3 has been identified by our laboratory in 1 Ca ucasian individual with congenital sensorineural hearing loss who had two clinic ally significant variants in another gene that likely explained the hearing loss (LMM unpublished data). This variant has also been identified in 2/66540 Europe an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs201018751); however its frequency is low enough to be consiste nt with a recessive carrier frequency. Computational prediction tools and conser vation analysis do not provide strong support for or against an impact to the pr otein. The presence of this variant in trans with a second variant in TMPRSS3 an d the segregation of the two variants in an affected sibling with hearing loss i ncreases the likelihood that the p.Met448Thr variant is pathogenic. In summary, although additional studies are required to fully establish its clinical signifi cance, this variant is likely pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided2not provided

Last Updated: Feb 20, 2024