NM_006941.4(SOX10):c.482G>A (p.Arg161His) AND Waardenburg syndrome type 2E

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 3, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001095698.15

Allele description [Variation Report for NM_006941.4(SOX10):c.482G>A (p.Arg161His)]

NM_006941.4(SOX10):c.482G>A (p.Arg161His)

Genes:

POLR2F:RNA polymerase II, I and III subunit F [Gene - OMIM - HGNC]
SOX10:SRY-box transcription factor 10 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

22q13.1

Genomic location:

Preferred name:

NM_006941.4(SOX10):c.482G>A (p.Arg161His)

HGVS:

NC_000022.11:g.37978082C>T
NG_007948.1:g.11451G>A
NM_001301130.2:c.294-8072C>T
NM_001301131.2:c.293+10912C>T
NM_001363825.1:c.*38+5772C>T
NM_006941.4:c.482G>AMANE SELECT
NP_008872.1:p.Arg161His
NP_008872.1:p.Arg161His
LRG_271t1:c.482G>A
LRG_271:g.11451G>A
LRG_271p1:p.Arg161His
NC_000022.10:g.38374089C>T
NC_000022.10:g.38374089C>T
NM_006941.3:c.482G>A

Protein change:

R161H

Links:

dbSNP: rs750566714

NCBI 1000 Genomes Browser:

rs750566714

Molecular consequence:

NM_001301130.2:c.294-8072C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001301131.2:c.293+10912C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001363825.1:c.*38+5772C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_006941.4:c.482G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Waardenburg syndrome type 2E (WS2E)
Synonyms:: WAARDENBURG SYNDROME, TYPE 2E, WITH OR WITHOUT NEUROLOGIC INVOLVEMENT; WS2E, WITH OR WITHOUT NEUROLOGIC INVOLVEMENT; HYPOGONADOTROPIC HYPOGONADISM WITH ANOSMIA AND DEAFNESS, WITH OR WITHOUT HYPOPIGMENTATION
Identifiers:: MONDO: MONDO:0012698; MedGen: C2700405; Orphanet: 3440; OMIM: 611584

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001251510	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	paternal	research	PubMed (2) [See all records that cite these PMIDs] 21898658, 25741868
SCV001478233	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2019)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003845146	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Feb 23, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 31152317, 33597575, 32853555, 28000701, 21898658, 27240497, 33865100, 33442024, 34142234, 32908489 Citation Link,
SCV004244346	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 3, 2024)	paternal	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	paternal	yes	1	not provided	not provided	not provided	not provided	clinical testing, research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The etiological evaluation of sensorineural hearing loss in children.

van Beeck Calkoen EA, Engel MSD, van de Kamp JM, Yntema HG, Goverts ST, Mulder MF, Merkus P, Hensen EF.

Eur J Pediatr. 2019 Aug;178(8):1195-1205. doi: 10.1007/s00431-019-03379-8. Epub 2019 May 31.

PubMed [citation]

PMID:: 31152317
PMCID:: PMC6647487

Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach.

Wang J, Xiang J, Chen L, Luo H, Xu X, Li N, Cui C, Xu J, Song N, Peng J, Peng Z.

Sci Rep. 2021 Feb 17;11(1):4036. doi: 10.1038/s41598-021-83493-6.

PubMed [citation]

PMID:: 33597575
PMCID:: PMC7889619

See all PubMed Citations (11)

Details of each submission

From UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill - NSIGHT-NC NEXUS, SCV001251510.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	research	PubMed (2)

Description

This SOX10 c.482G>A (p.R161H) variant has been reported previously in one individual with Waardenburg syndrome 2 (PMID: 21898658).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

From Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital, SCV001478233.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	inherited	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003845146.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004244346.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Criteria applied: PM1,PM2,PM5,PP3,PS2,PS4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	paternal	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 1, 2024

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