ClinVar Genomic variation as it relates to human health
NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)
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.961C>T (p.Arg321Ter)
Variation ID: 14276 Accession: VCV000014276.49
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p13 3: 69956460 (GRCh38) [ NCBI UCSC ] 3: 70005611 (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 Jan 13, 2017 Apr 15, 2024 Sep 1, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001354604.2:c.961C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001341533.1:p.Arg321Ter nonsense NM_000248.4:c.640C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000239.1:p.Arg214Ter nonsense NM_001184967.2:c.787C>T NP_001171896.1:p.Arg263Ter nonsense NM_001354605.2:c.958C>T NP_001341534.1:p.Arg320Ter nonsense NM_001354606.2:c.940C>T NP_001341535.1:p.Arg314Ter nonsense NM_001354607.2:c.892C>T NP_001341536.1:p.Arg298Ter nonsense NM_001354608.2:c.787C>T NP_001341537.1:p.Arg263Ter nonsense NM_006722.3:c.940C>T NP_006713.1:p.Arg314Ter nonsense NM_198158.3:c.622C>T NP_937801.1:p.Arg208Ter nonsense NM_198159.3:c.943C>T NP_937802.1:p.Arg315Ter nonsense NM_198177.3:c.895C>T NP_937820.1:p.Arg299Ter nonsense NM_198178.3:c.454C>T NP_937821.2:p.Arg152Ter nonsense NC_000003.12:g.69956460C>T NC_000003.11:g.70005611C>T NG_011631.1:g.221979C>T LRG_776:g.221979C>T LRG_776t1:c.640C>T LRG_776p1:p.Arg214Ter - Protein change
- R214*, R315*, R152*, R298*, R263*, R314*, R320*, R208*, R299*, R321*
- Other names
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- Canonical SPDI
- NC_000003.12:69956459:C:T
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
663 | 688 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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 (4) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000015346.35 | |
Pathogenic (1) |
no assertion criteria provided
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Jun 10, 2016 | RCV000414854.4 | |
Pathogenic (1) |
criteria provided, single submitter
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May 27, 2014 | RCV000415265.4 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 1, 2022 | RCV001200166.20 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 10, 2021 | RCV001813988.3 |
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
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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
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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
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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
(May 27, 2014)
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criteria provided, single submitter
Method: clinical testing
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Heterochromia iridis
Poliosis Prelingual sensorineural hearing impairment
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000493023.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Jul 14, 2017)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 2A
Affected status: yes
Allele origin:
unknown
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Accession: SCV001244760.1
First in ClinVar: May 04, 2020 Last updated: May 04, 2020 |
Comment:
A heterozygous nonsense variant was identified, NM_000248.3(MITF):c.640C>T in exon 7 of MITF. This nonsense variant is predicted to create a change of an arginine to … (more)
A heterozygous nonsense variant was identified, NM_000248.3(MITF):c.640C>T in exon 7 of MITF. This nonsense variant is predicted to create a change of an arginine to a stop at amino acid position 214, NP_000239.1(MITF):p.(Arg214*). This is predicted to result in loss of protein function either through truncation (half of the protein, including a helix-loop-helix domain and a MiT/TRFE transcription factor domain) or nonsense-mediated decay. This variant is not present in the gnomAD population database. It has been previously reported as a pathogenic variant in patients with Waardenburg syndrome (ClinVar). In addition, functional studies show that this variant causes loss of DNA binding activity and failure of transcription activity (Nobukuni. et al., (1996)). Other truncating variants downstream of c.640C>T in MITF have also been reported as pathogenic in individuals with Waardenburg syndrome. Subsequent testing of this patients parents indicates the variant is due to a de novo event. Based on current information, this variant has been classified as PATHOGENIC. (less)
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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: SCV001478207.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
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Pathogenic
(Aug 01, 2022)
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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: SCV002028678.3
First in ClinVar: Nov 29, 2021 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect due to inhibition of DNA binding and subsequent promoter activation (Nobukuni et al., 1996; Grill et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23787126, 25525159, 9856573, 29293505, 31827275, 8659547, 31850270, 33297549, 32422366) (less)
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Pathogenic
(Jul 10, 2021)
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criteria provided, single submitter
Method: clinical testing
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Ear malformation
Affected status: yes
Allele origin:
germline
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Kariminejad - Najmabadi Pathology & Genetics Center
Accession: SCV001755250.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 2A
Affected status: yes
Allele origin:
germline
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3billion
Accession: SCV002572721.1
First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. Stop-gained (nonsense) is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000014276 / PMID: 8659547). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Aortic aneurysm (present)
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Pathogenic
(Apr 01, 2020)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371056.18
First in ClinVar: Jul 16, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(Jun 10, 2016)
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no assertion criteria provided
Method: clinical testing
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Hearing loss
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV000492552.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
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Pathogenic
(Dec 04, 1998)
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no assertion criteria provided
Method: literature only
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WAARDENBURG SYNDROME, TYPE 2A
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000035605.4
First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020 |
Comment on evidence:
Lalwani et al. (1998) reported a 3-generation Indian family with a point mutation in the MITF gene causing Waardenburg syndrome type 2A (WS2A; 193510). Mutation … (more)
Lalwani et al. (1998) reported a 3-generation Indian family with a point mutation in the MITF gene causing Waardenburg syndrome type 2A (WS2A; 193510). Mutation screening of the MITF gene showed a 760C-T transition resulting in an arg214-to-ter nonsense mutation, predicted to result in a truncated MITF protein. The mutation occurred in a CpG dinucleotide. The R214X mutation was reported earlier in a northern European family by Nobukuni et al. (1996). Comparison of the phenotype of the 2 families demonstrated a significant difference in pigmentary disturbance of the eye. In both families, hearing loss was the most common finding, followed by ocular pigmentary disturbance. Heterochromia iridis occurred in 8 of 11 affected members of the Indian family and in 4 of 14 affected members of the European family. (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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Point mutation in the MITF gene causing Waardenburg syndrome type II in a three-generation Indian family. | Lalwani AK | American journal of medical genetics | 1998 | PMID: 9856573 |
Analyses of loss-of-function mutations of the MITF gene suggest that haploinsufficiency is a cause of Waardenburg syndrome type 2A. | Nobukuni Y | American journal of human genetics | 1996 | PMID: 8659547 |
Text-mined citations for rs104893746 ...
HelpRecord last updated Apr 15, 2024
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.