VCV000545639.5 - ClinVar

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

Interpretation:: Pathogenic/Likely pathogenic
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 3
First in ClinVar:: Dec 2, 2018
Most recent Submission:: Mar 26, 2023
Last evaluated:: Feb 28, 2023
Accession:: VCV000545639.5
Variation ID:: 545639
Description:: single nucleotide variant

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

Allele ID

536135

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

3p13

Genomic location

3: 69936760 (GRCh38) GRCh38 UCSC

3: 69985911 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_001354604.2:c.355-1062G>C MANE Select		intron variant
NM_000248.4:c.33+5G>C MANE Plus Clinical		intron variant
NM_001184967.2:c.199-1062G>C		intron variant
NM_001184968.2:c.33+5G>C		intron variant
NM_001354605.2:c.352-1062G>C		intron variant
NM_001354606.2:c.352-1062G>C		intron variant
NM_001354607.2:c.304-1062G>C		intron variant
NM_001354608.2:c.199-1062G>C		intron variant
NM_006722.3:c.352-1062G>C		intron variant
NM_198158.3:c.33+5G>C		intron variant
NM_198159.3:c.355-1062G>C		intron variant
NM_198177.3:c.307-1062G>C		intron variant
NM_198178.3:c.33+5G>C		intron variant
NC_000003.12:g.69936760G>C
NC_000003.11:g.69985911G>C
NG_011631.1:g.202279G>C
NG_050802.1:g.2463G>C
LRG_776:g.202279G>C
LRG_776t1:c.33+5G>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:69936759:G:C

Functional consequence

effect on RNA splicing [Variation Ontology VariO:0362]

Global minor allele frequency (GMAF)

Allele frequency

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD) 0.00001

Links

dbSNP: rs1236436555

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Waardenburg syndrome type 2	Likely pathogenic	1	no assertion criteria provided	-	RCV000722130.3
Melanoma, cutaneous malignant, susceptibility to, 8 Tietz syndrome Waardenburg syndrome type 2A	Pathogenic	1	criteria provided, single submitter	May 29, 2022	RCV002534250.1
Waardenburg syndrome type 2A	Likely pathogenic	1	criteria provided, single submitter	Feb 28, 2023	RCV003155262.1

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
MITF		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	515	539

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (May 29, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	- Melanoma, cutaneous malignant, susceptibility to, 8 - Waardenburg syndrome type 2A - Tietz syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV003525336.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (4) PubMed: 21373256‚ 30117279‚ 17576681‚ 9536098 Comment: This sequence change falls in intron 1 of the MITF gene. It does not directly change the encoded amino acid sequence of the MITF protein. … (more) This sequence change falls in intron 1 of the MITF gene. It does not directly change the encoded amino acid sequence of the MITF protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has been observed in individuals with clinical features of autosomal dominant Waardenburg Syndrome, type 2A (PMID: 21373256, 30117279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 545639). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 30117279). For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Feb 28, 2023)	criteria provided, single submitter (Li et al. (Genet Med. 2022)) Method: research	- Waardenburg syndrome type 2A Affected status: yes Allele origin: unknown	King Laboratory, University of Washington Accession: SCV003844122.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Publications: PubMed (1) PubMed: 36633841 Comment: 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 … (more) 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. (less)
Likely pathogenic (-)	no assertion criteria provided Method: research	- Waardenburg syndrome type 2 Affected status: yes Allele origin: germline	Institute for Human Genetics, University Medical Center Freiburg Accession: SCV000777908.1 First in ClinVar: Dec 02, 2018 Last updated: Dec 02, 2018	Comment: Our work describes a unique depigmentation phenotype in an Argentinean boy due to a MITF mutation. Our index patient was born to consanguineous parents (siblings) … (more) Our work describes a unique depigmentation phenotype in an Argentinean boy due to a MITF mutation. Our index patient was born to consanguineous parents (siblings) and thus is a homozygous carrier of the intronic mutation NM_000248.3:c.33+5G>C in the recognition context of the splice donor site specific to the melanocyte-specific M transcript variant of MITF. Several further family members are heterozygous carriers and presented a Waardenburg syndrome type 2A phenotype with typical variable expressivity. (less) Zygosity: 1 Homozygote Sex: male Geographic origin: Argentina

Comment:

This sequence change falls in intron 1 of the MITF gene. It does not directly change the encoded amino acid sequence of the MITF protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has been observed in individuals with clinical features of autosomal dominant Waardenburg Syndrome, type 2A (PMID: 21373256, 30117279). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 545639). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 30117279). For these reasons, this variant has been classified as Pathogenic.

Comment:

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.

Comment:

Our work describes a unique depigmentation phenotype in an Argentinean boy due to a MITF mutation. Our index patient was born to consanguineous parents (siblings) and thus is a homozygous carrier of the intronic mutation NM_000248.3:c.33+5G>C in the recognition context of the splice donor site specific to the melanocyte-specific M transcript variant of MITF. Several further family members are heterozygous carriers and presented a Waardenburg syndrome type 2A phenotype with typical variable expressivity.

Functional evidence

Functional consequence	Method	Result	Submitter	More information
effect on RNA splicing (VariO:0362)	Method not provided	Result not provided	Institute for Human Genetics, University Medical Center Freiburg Accession: SCV000777908.1 First in ClinVar: Dec 02, 2018 Last updated: Dec 02, 2018

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
Association of Genetic Diagnoses for Childhood-Onset Hearing Loss With Cochlear Implant Outcomes.	Carlson RJ	JAMA otolaryngology-- head & neck surgery	2023	PMID: 36633841
Homozygous intronic MITF mutation causes severe Waardenburg syndrome type 2A.	Rauschendorf MA	Pigment cell & melanoma research	2019	PMID: 30117279
Molecular Study of Three Lebanese and Syrian Patients with Waardenburg Syndrome and Report of Novel Mutations in the EDNRB and MITF Genes.	Haddad NM	Molecular syndromology	2011	PMID: 21373256
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs1236436555...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 02, 2023

ClinVar Genomic variation as it relates to human health

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

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

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs1236436555...