NM_006941.4(SOX10):c.482G>A (p.Arg161His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 27, 2023
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:: RCV001555269.13

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]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001776654	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Aug 27, 2023)	germline	clinical testing	Citation Link,
SCV003444389	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 3, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25077900, 27562378, 32908489, 21898658, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001776654

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Aug 27, 2023)

germline

clinical testing

Citation Link,

SCV003444389

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 3, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The prevalence of CHD7 missense versus truncating mutations is higher in patients with Kallmann syndrome than in typical CHARGE patients.

Marcos S, Sarfati J, Leroy C, Fouveaut C, Parent P, Metz C, Wolczynski S, Gérard M, Bieth E, Kurtz F, Verier-Mine O, Perrin L, Archambeaud F, Cabrol S, Rodien P, Hove H, Prescott T, Lacombe D, Christin-Maitre S, Touraine P, Hieronimus S, Dewailly D, et al.

J Clin Endocrinol Metab. 2014 Oct;99(10):E2138-43. doi: 10.1210/jc.2014-2110. Epub 2014 Jul 31. Erratum in: J Clin Endocrinol Metab. 2015 Jan;100(1):317.

PubMed [citation]

PMID:: 25077900

Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss.

Bademci G, Cengiz FB, Foster Ii J, Duman D, Sennaroglu L, Diaz-Horta O, Atik T, Kirazli T, Olgun L, Alper H, Menendez I, Loclar I, Sennaroglu G, Tokgoz-Yilmaz S, Guo S, Olgun Y, Mahdieh N, Bonyadi M, Bozan N, Ayral A, Ozkinay F, Yildirim-Baylan M, et al.

Sci Rep. 2016 Aug 26;6:31622. doi: 10.1038/srep31622.

PubMed [citation]

PMID:: 27562378
PMCID:: PMC4999867

See all PubMed Citations (5)

Details of each submission

From GeneDx, SCV001776654.2

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

Description

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, 31152317, 32853555, 36672963, 34142234, 33865100, 33442024, 33597575)

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

From Invitae, SCV003444389.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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).

#	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

Last Updated: May 1, 2024

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