NM_001354604.2(MITF):c.355-1062G>C AND Waardenburg syndrome type 2A

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Feb 28, 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:: RCV003155262.1

Allele description [Variation Report for NM_001354604.2(MITF):c.355-1062G>C]

NM_001354604.2(MITF):c.355-1062G>C

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.355-1062G>C

HGVS:

NC_000003.12:g.69936760G>C
NG_011631.1:g.202279G>C
NG_050802.1:g.2463G>C
NM_000248.4:c.33+5G>C
NM_001184967.2:c.199-1062G>C
NM_001184968.2:c.33+5G>C
NM_001354604.2:c.355-1062G>CMANE SELECT
NM_001354605.2:c.352-1062G>C
NM_001354606.2:c.352-1062G>C
NM_001354607.2:c.304-1062G>C
NM_001354608.2:c.199-1062G>C
NM_006722.3:c.352-1062G>C
NM_198158.3:c.33+5G>C
NM_198159.3:c.355-1062G>C
NM_198177.3:c.307-1062G>C
NM_198178.3:c.33+5G>C
LRG_776t1:c.33+5G>C
LRG_776:g.202279G>C
NC_000003.11:g.69985911G>C
NM_000248.3:c.33+5G>C

Links:

dbSNP: rs1236436555

NCBI 1000 Genomes Browser:

rs1236436555

Molecular consequence:

NM_000248.4:c.33+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001184967.2:c.199-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001184968.2:c.33+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354604.2:c.355-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354605.2:c.352-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354606.2:c.352-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354607.2:c.304-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354608.2:c.199-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_006722.3:c.352-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198158.3:c.33+5G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198159.3:c.355-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198177.3:c.307-1062G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_198178.3:c.33+5G>C - intron variant - [Sequence Ontology: SO:0001627]

Functional consequence:

effect on RNA splicing [Variation Ontology: 0362]

Condition(s)

Name:: Waardenburg syndrome type 2A (WS2A)
Synonyms:: WAARDENBURG SYNDROME WITHOUT DYSTOPIA CANTHORUM
Identifiers:: MONDO: MONDO:0008671; MedGen: C1860339; Orphanet: 3440; OMIM: 193510

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003844122	King Laboratory, University of Washington	criteria provided, single submitter (Li et al. (Genet Med. 2022))	Likely pathogenic (Feb 28, 2023)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 36633841, 35802133

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003844122

King Laboratory, University of Washington

criteria provided, single submitter

(Li et al. (Genet Med. 2022))

Likely pathogenic
(Feb 28, 2023)

unknown

research

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	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.

Carlson RJ, Walsh T, Mandell JB, Aburayyan A, Lee MK, Gulsuner S, Horn DL, Ou HC, Sie KCY, Mancl L, Rubinstein J, King MC.

JAMA Otolaryngol Head Neck Surg. 2023 Mar 1;149(3):212-222. doi: 10.1001/jamaoto.2022.4463.

PubMed [citation]

PMID:: 36633841
PMCID:: PMC9857764

Clinical evaluation and etiologic diagnosis of hearing loss: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

Li MM, Tayoun AA, DiStefano M, Pandya A, Rehm HL, Robin NH, Schaefer AM, Yoshinaga-Itano C; ACMG Professional Practice and Guidelines Committee. Electronic address: documents@acmg.net..

Genet Med. 2022 Jul;24(7):1392-1406. doi: 10.1016/j.gim.2022.03.018. Epub 2022 May 10.

PubMed [citation]

PMID:: 35802133

Details of each submission

From King Laboratory, University of Washington, SCV003844122.1

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

Description

This variant occurred in heterozygosity in an individual with Waardenburg syndrome including heterochromia iridis and bilateral sensorineural hearing loss of onset <18 years, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient's family has no other history of hearing loss. This variant is a single base pair substitution near the beginning of the first MITF intron. It is at a site that is completely conserved and is predicted to disrupt the donor splice site of MITF isoform M exon 1. At chr3:69985911, the sequence change is CAG|gtgaga > CAGgtgaca, NNSPLICE is 0.93 and 0.45 and MaxEnt is 9.22 and 5.49 for reference and mutant sequences, respectively. At the transcript level, the predicted consequence of this splice variant would be loss of expression of MITF isoform M from the mutant allele. As of January 2023, this variant has been reported previously in an individual with hearing loss (Waardenburg Type 2) and is currently classified as likely pathogenic on ClinVar, and it is found in 1 heterozygous individual on gnomAD. Based on the prediction that this variant leads to a splicing error and a truncated protein, previous classification as likely pathogenic, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic.

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

Last Updated: Feb 28, 2024

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