NM_181458.4(PAX3):c.202C>T (p.Arg68Trp) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jun 30, 2023
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:: RCV003660898.2

Allele description [Variation Report for NM_181458.4(PAX3):c.202C>T (p.Arg68Trp)]

NM_181458.4(PAX3):c.202C>T (p.Arg68Trp)

Gene:

PAX3:paired box 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q36.1

Genomic location:

Preferred name:

NM_181458.4(PAX3):c.202C>T (p.Arg68Trp)

Other names:

NM_181458.3:c.202C>T, p.(Arg68Trp)

HGVS:

NC_000002.12:g.222297097G>A
NG_011632.1:g.6885C>T
NG_021186.1:g.3951G>A
NM_000438.6:c.202C>T
NM_001127366.3:c.202C>T
NM_013942.5:c.202C>T
NM_181457.4:c.202C>T
NM_181458.4:c.202C>TMANE SELECT
NM_181459.4:c.202C>T
NM_181460.4:c.202C>T
NM_181461.4:c.202C>T
NP_000429.2:p.Arg68Trp
NP_001120838.1:p.Arg68Trp
NP_039230.1:p.Arg68Trp
NP_852122.1:p.Arg68Trp
NP_852123.1:p.Arg68Trp
NP_852124.1:p.Arg68Trp
NP_852125.1:p.Arg68Trp
NP_852126.1:p.Arg68Trp
NC_000002.11:g.223161816G>A

Protein change:

R68W

Links:

dbSNP: rs2106203892

NCBI 1000 Genomes Browser:

rs2106203892

Molecular consequence:

NM_000438.6:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127366.3:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_013942.5:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181457.4:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181458.4:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181459.4:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181460.4:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_181461.4:c.202C>T - 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
SCV004374561	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20127975, 32747562, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004374561

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 30, 2023)

germline

clinical testing

PubMed (3)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Review and update of mutations causing Waardenburg syndrome.

Pingault V, Ente D, Dastot-Le Moal F, Goossens M, Marlin S, Bondurand N.

Hum Mutat. 2010 Apr;31(4):391-406. doi: 10.1002/humu.21211. Review.

PubMed [citation]

PMID:: 20127975

Genomic analysis of inherited hearing loss in the Palestinian population.

Abu Rayyan A, Kamal L, Casadei S, Brownstein Z, Zahdeh F, Shahin H, Canavati C, Dweik D, Jaraysa T, Rabie G, Carlson RJ, Gulsuner S, Lee MK, Avraham KB, Walsh T, King MC, Kanaan MN.

Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20070-20076. doi: 10.1073/pnas.2009628117. Epub 2020 Aug 3.

PubMed [citation]

PMID:: 32747562
PMCID:: PMC7443947

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004374561.1

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

Description

This variant disrupts the p.Arg68 amino acid residue in PAX3. Other variant(s) that disrupt this residue have been observed in individuals with PAX3-related conditions (PMID: 20127975), which suggests that this may be a clinically significant amino acid residue. 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 PAX3 protein function. ClinVar contains an entry for this variant (Variation ID: 1299308). This missense change has been observed in individuals with Waardenburg syndrome (PMID: 32747562; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 68 of the PAX3 protein (p.Arg68Trp). 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: Sep 29, 2024

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