NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del) AND Waardenburg syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 1, 2019
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:: RCV000826199.4

Allele description [Variation Report for NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)]

NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

3p13

Genomic location:

Preferred name:

NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)

HGVS:

NC_000003.12:g.69956463AGA[2]
NG_011631.1:g.221982AGA[2]
NM_000248.4:c.643AGA[2]
NM_001184967.2:c.790AGA[2]
NM_001354604.2:c.964AGA[2]MANE SELECT
NM_001354605.2:c.961AGA[2]
NM_001354606.2:c.943AGA[2]
NM_001354607.2:c.895AGA[2]
NM_001354608.2:c.790AGA[2]
NM_006722.3:c.943AGA[2]
NM_198158.3:c.625AGA[2]
NM_198159.3:c.946AGA[2]
NM_198177.3:c.898AGA[2]
NM_198178.3:c.457AGA[2]
NP_000239.1:p.Arg217del
NP_001171896.1:p.Arg266del
NP_001341533.1:p.Arg324del
NP_001341534.1:p.Arg323del
NP_001341535.1:p.Arg317del
NP_001341536.1:p.Arg301del
NP_001341537.1:p.Arg266del
NP_006713.1:p.Arg317del
NP_937801.1:p.Arg211del
NP_937802.1:p.Arg318del
NP_937820.1:p.Arg302del
NP_937821.2:p.Arg155del
LRG_776t1:c.643AGA[2]
LRG_776t1:c.649_651del
LRG_776:g.221982AGA[2]
NC_000003.11:g.70005614AGA[2]
NC_000003.11:g.70005620_70005622delAGA
NM_000248.3:c.643AGA[2]
NM_000248.3:c.643AGA[2]
NM_000248.3:c.649_651del
NM_000248.3:c.649_651delAGA
NM_000248.3:c.649_651delAGA
NM_001354604.2:c.970_972delMANE SELECT
p.Arg217del

Protein change:

R155del; ARG217DEL

Links:

OMIM: 156845.0003; dbSNP: rs1553704814

NCBI 1000 Genomes Browser:

rs1553704814

Molecular consequence:

NM_000248.4:c.643AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001184967.2:c.790AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354604.2:c.964AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354605.2:c.961AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354606.2:c.943AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354607.2:c.895AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_001354608.2:c.790AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_006722.3:c.943AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198158.3:c.625AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198159.3:c.946AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198177.3:c.898AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]
NM_198178.3:c.457AGA[2] - inframe_deletion - [Sequence Ontology: SO:0001822]

Observations:

Condition(s)

Name:: Waardenburg syndrome
Synonyms:: Van der Hoeve Halbertsma Waardenburg Gualdi Syndrome; Ptosis-Epicanthus Syndrome; Mende Syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0018094; MedGen: C3266898; OMIM: PS193500

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000967750	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 1, 2019)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 20478267, 29531335, 26781036, 8589691, 23787126, 29115496, 22258527, 24194866, 20485200, 27073475, 29094203, 27889061, 24033266

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000967750

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Pathogenic
(Mar 1, 2019)

germline

clinical testing

PubMed (13)
[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	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome.

Chen H, Jiang L, Xie Z, Mei L, He C, Hu Z, Xia K, Feng Y.

Biochem Biophys Res Commun. 2010 Jun 18;397(1):70-4. doi: 10.1016/j.bbrc.2010.05.066. Epub 2010 May 15.

PubMed [citation]

PMID:: 20478267

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations.

Wang XP, Liu YL, Mei LY, He CF, Niu ZJ, Sun J, Zhao YL, Feng Y, Zhang H.

J Hum Genet. 2018 May;63(5):639-646. doi: 10.1038/s10038-018-0425-z. Epub 2018 Mar 12.

PubMed [citation]

PMID:: 29531335
PMCID:: PMC5915419

See all PubMed Citations (13)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000967750.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (13)

Description

The p.Arg217del variant in MITF is an in-frame deletion of an arginine and has been reported in >10 individuals with type 2 Waardenburg/Tietz syndrome, including at least 2 individuals who were apparently de novo without maternity and paternity confirmation (Chen 2010, Chen 2016, Hai 2017, Leger 2012, Shi 2016, Shigemura 2010, Tassabehji 1995, Wang 2018, Yang 2013). One individual with COMMAD syndrome has also been described (George 2016). The variant segregated in 9 affected family members, including the two family members of the proband with COMMAD syndrome who had Waardenburg syndrome (George 2016). In vitro functional studies have shown that the p.Arg217del results in inability of MITF to bind DNA and activate melanocyte-specific promotors, and the p.Arg217del variant represents the mouse equivalent mutation in the microphthalmia mi/mi mouse (George 2016, Grill 2013, Shigemura 2010, Wang 2018, Tassabehji 1995). This variant was absent from large population studies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant type 2 Waardenburg/Tietz syndrome based on the evidence outlined above. ACMG/AMP criteria applied: PS3, PS4, PM6_Strong, PP1_Strong, PM2, PP4, PM4_Supporting.

#	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	1	not provided

Last Updated: Feb 25, 2023

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