NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter) AND Rare genetic deafness

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 12, 2016
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:: RCV000218716.4

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]

Observations:

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271397	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 12, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 15284851, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271397

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Jan 12, 2016)

germline

clinical testing

PubMed (2)
[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	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Nonsense-mediated decay approaches the clinic.

Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE.

Nat Genet. 2004 Aug;36(8):801-8. Review.

PubMed [citation]

PMID:: 15284851

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, SCV000271397.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Arg371X variant in MITF has been identified by our laboratory in one indiv idual with hearing loss, which is assumed to have occurred de novo. It has not been reported in large population studies. This nonsense variant leads to a pr emature termination codon at position 371 and is located 51 nucleotides from the end of the penultimate (second to last) exon. Therefore, this variant is expect ed to undergo nonsense mediated mRNA decay (NMD) (Holbrook 2004) resulting in a n absent protein. However, due to its close location to the penultimate intron it could escape NMD and leading to a truncated protein. Heterozygous loss of fu nction variants in the MITF gene are well described in individuals with Waardenb urg syndrome. In summary, the p.Arg371X variant meets the criteria to be classi fied as pathogenic for hearing loss in an autosomal dominant manner.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		1	not provided	1	not provided

Last Updated: May 16, 2025

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