VCV000014276.46 - ClinVar

NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)

Interpretation:: Pathogenic
Review status:: criteria provided, multiple submitters, no conflicts
Submissions:: 9
First in ClinVar:: Jan 13, 2017
Most recent Submission:: Nov 20, 2023
Last evaluated:: Sep 1, 2022
Accession:: VCV000014276.46
Variation ID:: 14276
Description:: single nucleotide variant

NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)

Allele ID

29315

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

3p13

Genomic location

3: 69956460 (GRCh38) GRCh38 UCSC

3: 70005611 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_001354604.2:c.961C>T MANE Select	NP_001341533.1:p.Arg321Ter	nonsense
NM_000248.4:c.640C>T MANE Plus Clinical	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

... more HGVS ... less HGVS

Protein change

R214*, R315*, R152*, R298*, R263*, R314*, R320*, R208*, R299*, R321*

Other names

Canonical SPDI

NC_000003.12:69956459:C:T

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

Links

ClinGen: CA123834

OMIM: 156845.0007

dbSNP: rs104893746

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Waardenburg syndrome type 2A	Pathogenic	4	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000015346.35
Hearing impairment	Pathogenic	1	no assertion criteria provided	Jun 10, 2016	RCV000414854.4
Heterochromia iridis Poliosis Prelingual sensorineural hearing impairment	Pathogenic	1	criteria provided, single submitter	May 27, 2014	RCV000415265.4
not provided	Pathogenic	2	criteria provided, multiple submitters, no conflicts	Aug 1, 2022	RCV001200166.17
Abnormality of the ear	Pathogenic	1	criteria provided, single submitter	Jul 10, 2021	RCV001813988.3

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 (Jan 01, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Waardenburg syndrome type 2A Affected status: yes Allele origin: de novo	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
Pathogenic (Jul 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Abnormality of the ear Affected status: yes Allele origin: germline	Kariminejad - Najmabadi Pathology & Genetics Center Accession: SCV001755250.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Pathogenic (Aug 01, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	- Not Provided Affected status: yes Allele origin: germline	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)
Pathogenic (May 27, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Heterochromia iridis - Poliosis - Prelingual sensorineural hearing impairment Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000493023.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Jul 14, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Waardenburg syndrome type 2A Affected status: yes Allele origin: unknown	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)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	- Waardenburg syndrome type 2A Affected status: yes Allele origin: germline	3billion Accession: SCV002572721.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (1) PubMed: 8659547 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) Zygosity: 1 Single Heterozygote
Pathogenic (Apr 01, 2020)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	- not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001371056.15 First in ClinVar: Jul 16, 2020 Last updated: Nov 20, 2023	Number of individuals with the variant: 1
Pathogenic (Jun 10, 2016)	no assertion criteria provided Method: clinical testing	- Hearing loss Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV000492552.1 First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017
Pathogenic (Dec 04, 1998)	no assertion criteria provided Method: literature only	- WAARDENBURG SYNDROME, TYPE 2A Affected status: not provided Allele origin: germline	OMIM Accession: SCV000035605.4 First in ClinVar: Apr 04, 2013 Last updated: Feb 06, 2020	Publications: PubMed (2) PubMed: 9856573‚ 8659547 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)

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 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)

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 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.

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 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.

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.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
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...

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 Nov 20, 2023

ClinVar Genomic variation as it relates to human health

NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)

NM_001354604.2(MITF):c.961C>T (p.Arg321Ter)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs104893746...