ClinVar Genomic variation as it relates to human health
NM_006941.4(SOX10):c.482G>A (p.Arg161His)
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.
Pathogenic(1); Likely pathogenic(3); Uncertain significance(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006941.4(SOX10):c.482G>A (p.Arg161His)
Variation ID: 873468 Accession: VCV000873468.12
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 22q13.1 22: 37978082 (GRCh38) [ NCBI UCSC ] 22: 38374089 (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 May 31, 2020 Sep 16, 2024 Jun 10, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006941.4:c.482G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_008872.1:p.Arg161His missense NM_001301130.2:c.294-8072C>T intron variant NM_001301131.2:c.293+10912C>T intron variant NM_001363825.1:c.*38+5772C>T intron variant NC_000022.11:g.37978082C>T NC_000022.10:g.38374089C>T NG_007948.1:g.11451G>A LRG_271:g.11451G>A LRG_271t1:c.482G>A LRG_271p1:p.Arg161His - Protein change
- R161H
- Other names
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- Canonical SPDI
- NC_000022.11:37978081: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.
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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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SOX10 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
- | 434 | |
POLR2F | - | - |
GRCh38 GRCh37 |
5 | 440 |
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
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
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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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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 3, 2024 | RCV001095698.15 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jun 10, 2024 | RCV001555269.15 |
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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Uncertain significance
(-)
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criteria provided, single submitter
Method: research
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Waardenburg syndrome type 2E
Affected status: yes
Allele origin:
paternal
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251510.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This SOX10 c.482G>A (p.R161H) variant has been reported previously in one individual with Waardenburg syndrome 2 (PMID: 21898658).
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 2E
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: SCV001478233.1
First in ClinVar: Jan 30, 2021 Last updated: Jan 30, 2021 |
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Likely pathogenic
(Feb 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 2E
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003845146.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: SOX10 c.482G>A (p.Arg161His) results in a non-conservative amino acid change located in the High mobility group box domain (IPR009071) of the encoded protein … (more)
Variant summary: SOX10 c.482G>A (p.Arg161His) results in a non-conservative amino acid change located in the High mobility group box domain (IPR009071) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.2e-06 in 237008 control chromosomes (gnomAD). c.482G>A has been reported in the literature in one individual affected with Waardenburg syndrome 2 (Chaoui_2011) and individuals affected with hearing loss (Zazo Seco_2016, Roman_2020, Wang_2021), including one de novo occurrence (Zazo Seco_2016). These data indicate that the variant is likely to be associated with disease. At least one functional study reports this variant results in activating the Cx32 promoter in a manner similar to that of the wild-type protein, but reducing its activity on MITF prmoter and RET enchancer and partially protein redistributed in the cytoplasm. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance, likely pathogenic and pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Jan 03, 2024)
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criteria provided, single submitter
Method: clinical testing
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Waardenburg syndrome type 2E
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
paternal
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV004244346.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
Criteria applied: PM1,PM2,PM5,PP3,PS2,PS4
Clinical Features:
Seizure (present) , Global developmental delay (present)
Sex: male
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Uncertain significance
(Jul 03, 2022)
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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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003444389.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant … (more)
In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Arg161 amino acid residue in SOX10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25077900, 27562378, 32908489). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SOX10 function (PMID: 21898658). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 873468). This missense change has been observed in individual(s) with Waardenburg syndrome (PMID: 21898658). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 161 of the SOX10 protein (p.Arg161His). (less)
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Likely pathogenic
(Jun 10, 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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GeneDx
Accession: SCV001776654.3
First in ClinVar: Aug 13, 2021 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 21898658, 32853555, 36672963, 34142234, 33865100, 33442024, 33597575, 31152317) (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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Analysis of genotype-phenotype relationships in 90 Chinese probands with Waardenburg syndrome. | Wang G | Human genetics | 2022 | PMID: 34142234 |
A de novo mutation of the SOX10 gene associated with inner ear malformation in a Guangxi family with Waardenburg syndrome type II. | Niu Z | International journal of pediatric otorhinolaryngology | 2021 | PMID: 33865100 |
Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach. | Wang J | Scientific reports | 2021 | PMID: 33597575 |
Phenotypic continuum between Waardenburg syndrome and idiopathic hypogonadotropic hypogonadism in humans with SOX10 variants. | Rojas RA | Genetics in medicine : official journal of the American College of Medical Genetics | 2021 | PMID: 33442024 |
Targeted Next-Generation Sequencing Identifies Separate Causes of Hearing Loss in One Deaf Family and Variable Clinical Manifestations for the p.R161C Mutation in SOX10. | Yu X | Neural plasticity | 2020 | PMID: 32908489 |
Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
The etiological evaluation of sensorineural hearing loss in children. | van Beeck Calkoen EA | European journal of pediatrics | 2019 | PMID: 31152317 |
The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands. | Zazo Seco C | European journal of human genetics : EJHG | 2017 | PMID: 28000701 |
Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss. | Bademci G | Scientific reports | 2016 | PMID: 27562378 |
Waardenburg syndrome type II in a Chinese patient caused by a novel nonsense mutation in the SOX10 gene. | Ma J | International journal of pediatric otorhinolaryngology | 2016 | PMID: 27240497 |
The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients. | Marcos S | The Journal of clinical endocrinology and metabolism | 2014 | PMID: 25077900 |
Identification and functional analysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. | Chaoui A | Human mutation | 2011 | PMID: 21898658 |
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Text-mined citations for rs750566714 ...
HelpRecord last updated Oct 08, 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.