ClinVar Genomic variation as it relates to human health
NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)
Variation ID: 14272 Accession: VCV000014272.10
- Type and length
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Microsatellite, 3 bp
- Location
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Cytogenetic: 3p13 3: 69956461-69956463 (GRCh38) [ NCBI UCSC ] 3: 70005612-70005614 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 19, 2017 Feb 18, 2023 Feb 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001354604.2:c.964AGA[2] MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001341533.1:p.Arg324del inframe deletion NM_001354604.2:c.970_972del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000248.4:c.643AGA[2] MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000239.1:p.Arg217del inframe deletion NM_000248.3:c.649_651del NM_000248.3:c.649_651delAGA NM_001184967.2:c.790AGA[2] NP_001171896.1:p.Arg266del inframe deletion NM_001354605.2:c.961AGA[2] NP_001341534.1:p.Arg323del inframe deletion NM_001354606.2:c.943AGA[2] NP_001341535.1:p.Arg317del inframe deletion NM_001354607.2:c.895AGA[2] NP_001341536.1:p.Arg301del inframe deletion NM_001354608.2:c.790AGA[2] NP_001341537.1:p.Arg266del inframe deletion NM_006722.3:c.943AGA[2] NP_006713.1:p.Arg317del inframe deletion NM_198158.3:c.625AGA[2] NP_937801.1:p.Arg211del inframe deletion NM_198159.3:c.946AGA[2] NP_937802.1:p.Arg318del inframe deletion NM_198177.3:c.898AGA[2] NP_937820.1:p.Arg302del inframe deletion NM_198178.3:c.457AGA[2] NP_937821.2:p.Arg155del inframe deletion NC_000003.12:g.69956463AGA[2] NC_000003.11:g.70005614AGA[2] NG_011631.1:g.221982AGA[2] LRG_776:g.221982AGA[2] LRG_776t1:c.643AGA[2] LRG_776t1:c.649_651del - Protein change
- R217del, R317del, R155del, R266del, R301del, R302del, R211del, R318del, R323del, R324del
- Other names
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- Canonical SPDI
- NC_000003.12:69956460:GAAGAAGAAGA:GAAGAAGA
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MITF | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
679 | 704 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000015342.28 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2008 | RCV000498643.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 1, 2019 | RCV000826199.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 1, 2019 | RCV001290155.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 9, 2023 | RCV001785452.2 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Tietz syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781744.1
First in ClinVar: Aug 19, 2017 Last updated: Aug 19, 2017 |
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Pathogenic
(Mar 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000967750.2
First in ClinVar: Aug 26, 2019 Last updated: Aug 26, 2019 |
Comment:
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 … (more)
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. (less)
Number of individuals with the variant: 1
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Pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 2A
Affected status: yes
Allele origin:
de novo
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV001478212.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
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Pathogenic
(Feb 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002027888.2
First in ClinVar: Nov 29, 2021 Last updated: Feb 18, 2023 |
Comment:
Observed in other patients with Waardenburg syndrome in published literature (Chen et al., 2010; Shi et al., 2016); Published functional studies demonstrate a damaging effect … (more)
Observed in other patients with Waardenburg syndrome in published literature (Chen et al., 2010; Shi et al., 2016); Published functional studies demonstrate a damaging effect on DNA binding (Grill et al., 2013; Wang et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of 1 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 22258527, 20485200, 29094203, 27889061, 20478267, 23787126, 24194866, 8589691, 29531335, 30978479, 27604145, 26781036, 26663054, 29938923, 8622664, 29115496, 27073475, 32005694, 34142234) (less)
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tietz syndrome
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572523.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant leading to inframe deletion located in a nonrepeat region is predicted to change … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant leading to inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 23787126). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 22258527). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000014272/ PMID: 8589691). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Hearing impairment (present)
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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TIETZ ALBINISM-DEAFNESS SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035601.3
First in ClinVar: Apr 04, 2013 Last updated: Aug 19, 2017 |
Comment on evidence:
In a family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely … (more)
In a family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain. Following the mouse precedent, they labeled this mutation R217del, although from the DNA and protein sequences one could not say which of the 4 arginines was deleted. Amiel et al. (1998) noted that although the affected mother and son fulfilled diagnostic criteria for Waardenburg syndrome type 2 (see 193510), they more closely resembled the family reported by Tietz (1963). In a 24-year-old woman with Tietz syndrome, Izumi et al. (2008) identified heterozygosity for the R217del mutation in the MITF gene. The authors noted that dimerization between mutant and wildtype protein would reduce the number of intact wildtype dimers with access to the nucleus to 25% of normal. Histologic examination of skin biopsy specimens revealed the presence of melanocytes, suggesting that the migration of melanocyte stem cells from the neural crest to the epidermal layer occurred normally. In the hypopigmented regions, however, a reduction in the number of melanosomes in keratinocytes adjacent to the melanocytes suggested a disruption in the transfer of melanosomes from the melanocytes to the keratinocytes; and in the hyperpigmented regions, an increase in the number of melanosomes in the keratinocytes adjacent to HMB45-positive melanocytes pointed to a high level of melanogenesis. In a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), George et al. (2016) identified compound heterozygosity for mutations in the MITF gene: the first was a 3-bp deletion (c.952_954delAGA), which they stated corresponded to Arg318del in the MITF-A isoform and to Arg217del in the MITF-M isoform; the second was a c.921G-C transversion, resulting in a lys307-to-asn (K307N; 156845.0010) substitution in isoform MITF-A. The proband's parents and 1 brother, who exhibited features of WS2A, were each heterozygous for 1 of the mutations. The K307N mutation was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Functional analysis showed that, unlike wildtype MITF, the R318del mutant did not migrate to the nucleus in transfected HEK293 cells or bind consensus M-box or E-box DNA sequences in vitro; in addition, this allele did not activate the tyrosinase (TYR; 606933) promoter or repress the FGF19 (603891) promoter in dual luciferase reporter assays. In comparison, the K307N allele was distributed equally between the nucleus and the cytoplasm and exhibited approximately 20% of the DNA-binding capability of wildtype MITF, but had significant transcriptional regulatory potential on TYR and FGF19 promoters. Coexpression of R318del and K307N in HEK293 cells resulted in migration of only 30% of MITF into the nucleus, whereas coexpression of mutant with wildtype protein resulted in 36% or 81% migration, respectively. DNA binding of co-in-vitro-translated R318del and K307N was less than 20% of that of wildtype MITF for consensus E-box and M-box elements; wildtype with R318del resulted in approximately 50% reduction of DNA binding, whereas wildtype with K307N bound both consensus elements better than wildtype. Transcriptional activation of the TYRP1 (115501) promoter was reduced more dramatically when increasing amounts of R318del were coexpressed with K307N than with wildtype. (less)
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Pathogenic
(Jul 01, 2008)
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no assertion criteria provided
Method: literature only
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COLOBOMA, OSTEOPETROSIS, MICROPHTHALMIA, MACROCEPHALY, ALBINISM, AND DEAFNESS
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000590793.1
First in ClinVar: Aug 20, 2017 Last updated: Aug 20, 2017 |
Comment on evidence:
In a family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely … (more)
In a family with partial albinism and sensorineural deafness (TADS; 103500), Tassabehji et al. (1995) identified the exact equivalent of the mouse microphthalmia mutation, namely a deletion of 1 of a run of 4 arginines in the basic domain. Following the mouse precedent, they labeled this mutation R217del, although from the DNA and protein sequences one could not say which of the 4 arginines was deleted. Amiel et al. (1998) noted that although the affected mother and son fulfilled diagnostic criteria for Waardenburg syndrome type 2 (see 193510), they more closely resembled the family reported by Tietz (1963). In a 24-year-old woman with Tietz syndrome, Izumi et al. (2008) identified heterozygosity for the R217del mutation in the MITF gene. The authors noted that dimerization between mutant and wildtype protein would reduce the number of intact wildtype dimers with access to the nucleus to 25% of normal. Histologic examination of skin biopsy specimens revealed the presence of melanocytes, suggesting that the migration of melanocyte stem cells from the neural crest to the epidermal layer occurred normally. In the hypopigmented regions, however, a reduction in the number of melanosomes in keratinocytes adjacent to the melanocytes suggested a disruption in the transfer of melanosomes from the melanocytes to the keratinocytes; and in the hyperpigmented regions, an increase in the number of melanosomes in the keratinocytes adjacent to HMB45-positive melanocytes pointed to a high level of melanogenesis. In a 5-year-old boy with coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD; 617306), George et al. (2016) identified compound heterozygosity for mutations in the MITF gene: the first was a 3-bp deletion (c.952_954delAGA), which they stated corresponded to Arg318del in the MITF-A isoform and to Arg217del in the MITF-M isoform; the second was a c.921G-C transversion, resulting in a lys307-to-asn (K307N; 156845.0010) substitution in isoform MITF-A. The proband's parents and 1 brother, who exhibited features of WS2A, were each heterozygous for 1 of the mutations. The K307N mutation was not found in the 1000 Genomes Project, dbSNP, Exome Variant Server, or ExAC databases. Functional analysis showed that, unlike wildtype MITF, the R318del mutant did not migrate to the nucleus in transfected HEK293 cells or bind consensus M-box or E-box DNA sequences in vitro; in addition, this allele did not activate the tyrosinase (TYR; 606933) promoter or repress the FGF19 (603891) promoter in dual luciferase reporter assays. In comparison, the K307N allele was distributed equally between the nucleus and the cytoplasm and exhibited approximately 20% of the DNA-binding capability of wildtype MITF, but had significant transcriptional regulatory potential on TYR and FGF19 promoters. Coexpression of R318del and K307N in HEK293 cells resulted in migration of only 30% of MITF into the nucleus, whereas coexpression of mutant with wildtype protein resulted in 36% or 81% migration, respectively. DNA binding of co-in-vitro-translated R318del and K307N was less than 20% of that of wildtype MITF for consensus E-box and M-box elements; wildtype with R318del resulted in approximately 50% reduction of DNA binding, whereas wildtype with K307N bound both consensus elements better than wildtype. Transcriptional activation of the TYRP1 (115501) promoter was reduced more dramatically when increasing amounts of R318del were coexpressed with K307N than with wildtype. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations. | Wang XP | Journal of human genetics | 2018 | PMID: 29531335 |
Prenatal diagnosis and genetic counseling for Waardenburg syndrome type I and II in Chinese families. | Wang L | Molecular medicine reports | 2018 | PMID: 29115496 |
Creation of miniature pig model of human Waardenburg syndrome type 2A by ENU mutagenesis. | Hai T | Human genetics | 2017 | PMID: 29094203 |
Biallelic Mutations in MITF Cause Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, and Deafness. | George A | American journal of human genetics | 2016 | PMID: 27889061 |
A novel mutation of the MITF gene in a family with Waardenburg syndrome type 2: A case report. | Shi Y | Experimental and therapeutic medicine | 2016 | PMID: 27073475 |
Clinical and genetic investigation of families with type II Waardenburg syndrome. | Chen Y | Molecular medicine reports | 2016 | PMID: 26781036 |
Genetic and phenotypic heterogeneity in Chinese patients with Waardenburg syndrome type II. | Yang S | PloS one | 2013 | PMID: 24194866 |
MITF mutations associated with pigment deficiency syndromes and melanoma have different effects on protein function. | Grill C | Human molecular genetics | 2013 | PMID: 23787126 |
Novel and recurrent non-truncating mutations of the MITF basic domain: genotypic and phenotypic variations in Waardenburg and Tietz syndromes. | Léger S | European journal of human genetics : EJHG | 2012 | PMID: 22258527 |
Effect of the mutant microphthalmia-associated transcription factor found in Tietz syndrome on the in vitro development of mast cells. | Shigemura T | Journal of pediatric hematology/oncology | 2010 | PMID: 20485200 |
Novel mutations of PAX3, MITF, and SOX10 genes in Chinese patients with type I or type II Waardenburg syndrome. | Chen H | Biochemical and biophysical research communications | 2010 | PMID: 20478267 |
Tietz syndrome: unique phenotype specific to mutations of MITF nuclear localization signal. | Izumi K | Clinical genetics | 2008 | PMID: 18510545 |
Mutation of the MITF gene in albinism-deafness syndrome (Tietz syndrome). | Amiel J | Clinical dysmorphology | 1998 | PMID: 9546825 |
The mutational spectrum in Waardenburg syndrome. | Tassabehji M | Human molecular genetics | 1995 | PMID: 8589691 |
A syndrome of deaf-mutism associated with albinism showing dominant autosomal inheritance. | TIETZ W | American journal of human genetics | 1963 | PMID: 13985019 |
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Text-mined citations for rs1553704814 ...
HelpRecord last updated Feb 25, 2023
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.