ClinVar Genomic variation as it relates to human health
NM_181458.4(PAX3):c.667C>T (p.Arg223Ter)
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_181458.4(PAX3):c.667C>T (p.Arg223Ter)
Variation ID: 503680 Accession: VCV000503680.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2q36.1 2: 222232203 (GRCh38) [ NCBI UCSC ] 2: 223096922 (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 Apr 2, 2018 Apr 15, 2024 Mar 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_181458.4:c.667C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_852123.1:p.Arg223Ter nonsense NM_001127366.3:c.664C>T NP_001120838.1:p.Arg222Ter nonsense NM_181457.4:c.667C>T NP_852122.1:p.Arg223Ter nonsense NM_181459.3:c.667C>T NM_181459.4:c.667C>T NP_852124.1:p.Arg223Ter nonsense NM_181460.4:c.667C>T NP_852125.1:p.Arg223Ter nonsense NM_181461.4:c.667C>T NP_852126.1:p.Arg223Ter nonsense NC_000002.12:g.222232203G>A NC_000002.11:g.223096922G>A NG_011632.1:g.71779C>T - Protein change
- R223*, R222*
- Other names
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- Canonical SPDI
- NC_000002.12:222232202:G:A
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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.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
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
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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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PAX3 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
286 | 374 |
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 (4) |
criteria provided, multiple submitters, no conflicts
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Mar 1, 2024 | RCV000599259.8 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2021 | RCV001290145.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 23, 2018 | RCV001335583.1 |
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
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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
(Feb 22, 2018)
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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: SCV000709897.1
First in ClinVar: Apr 02, 2018 Last updated: Apr 02, 2018 |
Comment:
The R223X nonsense variant has been reported previously in association with Waardenburg syndrome, including an apparently de novo occurrence (Jalilian et al., 2015; Sun et … (more)
The R223X nonsense variant has been reported previously in association with Waardenburg syndrome, including an apparently de novo occurrence (Jalilian et al., 2015; Sun et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is observed in 1/30782 (0.003%) alleles from individuals of South Asian background in large population cohorts (Lek et al., 2016). In summary, we consider this variant to be pathogenic. (less)
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Pathogenic
(Aug 04, 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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Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001467991.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
Comment on evidence:
PVS1, PS4
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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 1
Affected status: yes
Allele origin:
inherited
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Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Accession: SCV001478198.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
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Pathogenic
(Apr 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 3
Affected status: yes
Allele origin:
paternal
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Baylor Genetics
Accession: SCV001528762.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 8019556, 26275939, 27759048, … (more)
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 8019556, 26275939, 27759048, 25525159] (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: research
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Waardenburg syndrome type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Otorhinolaryngology Lab - LIM32, University of Sao Paulo School of Medicine Clinics Hospital
Accession: SCV001792239.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
Familial case: proband with bilateral profound sensorineural hearing loss, Telecanthus, nasal wings hypoplasia and hyperplasia of nasal root, and synophris, Blue hypoplastic irides and white … (more)
Familial case: proband with bilateral profound sensorineural hearing loss, Telecanthus, nasal wings hypoplasia and hyperplasia of nasal root, and synophris, Blue hypoplastic irides and white hair forelock. Paternal grandmother and paternal aunt are also carriers of this variant and affected by only facial dysmorphisms (less)
Observation 1:
Clinical Features:
Prelingual sensorineural hearing impairment (present) , Heterochromia iridis (present) , Telecanthus (present) , Abnormality of hair pigmentation (present) , Synophrys (present) , Abnormality of skin … (more)
Prelingual sensorineural hearing impairment (present) , Heterochromia iridis (present) , Telecanthus (present) , Abnormality of hair pigmentation (present) , Synophrys (present) , Abnormality of skin pigmentation (present) (less)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 2:
Clinical Features:
Telecanthus (present) , Abnormal facial shape (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
Observation 3:
Clinical Features:
Telecanthus (present) , Abnormal facial shape (present)
Family history: yes
Segregation observed: yes
Secondary finding: no
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Pathogenic
(Oct 01, 2021)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 1
Affected status: yes
Allele origin:
unknown
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV001976945.1
First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
Comment:
PVS1, PM1, PM2, PP3, PP4, PP5
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 1
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004171872.1
First in ClinVar: Dec 09, 2023 Last updated: Dec 09, 2023 |
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Pathogenic
(Apr 17, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002240644.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503680). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 503680). This premature translational stop signal has been observed in individual(s) with Waardenburg syndrome (PMID: 8019556, 30978479). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs772241382, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg223*) in the PAX3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PAX3 are known to be pathogenic (PMID: 20127975, 23512835). (less)
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Pathogenic
(Mar 01, 2024)
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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: SCV004811470.1
First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024 |
Comment:
PAX3: PVS1, PM2, PS4:Moderate
Number of individuals with the variant: 1
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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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Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss. | Batissoco AC | Human genetics | 2022 | PMID: 34599368 |
Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders. | Marinakis NM | American journal of medical genetics. Part A | 2021 | PMID: 34008892 |
A clinical and genetic study of 16 Japanese families with Waardenburg syndrome. | Minami SB | Gene | 2019 | PMID: 30978479 |
Molecular etiology and genotype-phenotype correlation of Chinese Han deaf patients with type I and type II Waardenburg Syndrome. | Sun L | Scientific reports | 2016 | PMID: 27759048 |
Molecular and clinical characterization of Waardenburg syndrome type I in an Iranian cohort with two novel PAX3 mutations. | Jalilian N | Gene | 2015 | PMID: 26275939 |
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. | Xiong HY | Science (New York, N.Y.) | 2015 | PMID: 25525159 |
Spectrum of novel mutations found in Waardenburg syndrome types 1 and 2: implications for molecular genetic diagnostics. | Wildhardt G | BMJ open | 2013 | PMID: 23512835 |
Review and update of mutations causing Waardenburg syndrome. | Pingault V | Human mutation | 2010 | PMID: 20127975 |
Mutations in PAX3 associated with Waardenburg syndrome type I. | Baldwin CT | Human mutation | 1994 | PMID: 8019556 |
Text-mined citations for rs772241382 ...
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.