NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter) AND Waardenburg syndrome type 2

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 6, 2024
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:: RCV005250037.1

Allele description [Variation Report for NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)]

NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)

Gene:

MITF:melanocyte inducing transcription factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p13

Genomic location:

Preferred name:

NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)

HGVS:

NC_000003.12:g.69959370C>T
NG_011631.1:g.224889C>T
NM_000248.4:c.808C>T
NM_001184967.2:c.955C>T
NM_001354604.2:c.1129C>TMANE SELECT
NM_001354605.2:c.1126C>T
NM_001354606.2:c.1108C>T
NM_001354607.2:c.1060C>T
NM_001354608.2:c.955C>T
NM_006722.3:c.1108C>T
NM_198158.3:c.790C>T
NM_198159.3:c.1111C>T
NM_198177.3:c.1063C>T
NM_198178.3:c.622C>T
NP_000239.1:p.Arg270Ter
NP_001171896.1:p.Arg319Ter
NP_001341533.1:p.Arg377Ter
NP_001341534.1:p.Arg376Ter
NP_001341535.1:p.Arg370Ter
NP_001341536.1:p.Arg354Ter
NP_001341537.1:p.Arg319Ter
NP_006713.1:p.Arg370Ter
NP_937801.1:p.Arg264Ter
NP_937802.1:p.Arg371Ter
NP_937820.1:p.Arg355Ter
NP_937821.2:p.Arg208Ter
LRG_776t1:c.808C>T
LRG_776:g.224889C>T
NC_000003.11:g.70008521C>T
NM_000248.3:c.808C>T
NM_198159.2:c.1111C>T
p.Arg371X

Protein change:

R208*

Links:

dbSNP: rs876657699

NCBI 1000 Genomes Browser:

rs876657699

Molecular consequence:

NM_000248.4:c.808C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001184967.2:c.955C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354604.2:c.1129C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354605.2:c.1126C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354606.2:c.1108C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354607.2:c.1060C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001354608.2:c.955C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_006722.3:c.1108C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198158.3:c.790C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198159.3:c.1111C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198177.3:c.1063C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_198178.3:c.622C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Waardenburg syndrome type 2
Identifiers:: MONDO: MONDO:0019517; MedGen: C2700265

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV005900465	Molecular Genetics, Royal Melbourne Hospital See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 6, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 7874167, 7874168, 9499424, 27759048, 38965328, 39107234, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005900465

Molecular Genetics, Royal Melbourne Hospital

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 6, 2024)

germline

clinical testing

PubMed (7)
[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

Citations

PubMed

Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene.

Tassabehji M, Newton VE, Read AP.

Nat Genet. 1994 Nov;8(3):251-5.

PubMed [citation]

PMID:: 7874167

Molecular basis of mouse microphthalmia (mi) mutations helps explain their developmental and phenotypic consequences.

Steingrímsson E, Moore KJ, Lamoreux ML, Ferré-D'Amaré AR, Burley SK, Zimring DC, Skow LC, Hodgkinson CA, Arnheiter H, Copeland NG, et al.

Nat Genet. 1994 Nov;8(3):256-63.

PubMed [citation]

PMID:: 7874168

See all PubMed Citations (7)

Details of each submission

From Molecular Genetics, Royal Melbourne Hospital, SCV005900465.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change in MITF is a nonsense variant predicted to create a premature stop codon, p.(Arg377*), in biologically relevant exon 9/10 expected to lead to nonsense-mediated decay in a gene in which loss-of-function is an established disease mechanism (PMID: 7874167, 7874168, 9499424, 27759048). This variant is absent from the population database gnomAD v4.1. This variant has been reported in multiple probands with deafness/syndromic deafness, and segregates with disease in a large four-generation family (PMID: 27759048, 38965328, 39107234; ClinVar: SCV001478214.1, SCV000271397.2). One of the individuals is a de novo occurrence the variant with unconfirmed parental relationships (ClinVar: SCV000271397.2). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.7.1, this variant is classified as PATHOGENIC. Following criteria are met: PM2_Supporting, PM6, PP1_Strong, PS4_Supporting, PVS1

#	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

Last Updated: May 16, 2025

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