NM_006941.4(SOX10):c.470C>T (p.Ala157Val) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Jan 20, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV002273922.10

Allele description [Variation Report for NM_006941.4(SOX10):c.470C>T (p.Ala157Val)]

NM_006941.4(SOX10):c.470C>T (p.Ala157Val)

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.470C>T (p.Ala157Val)

HGVS:

NC_000022.11:g.37978094G>A
NG_007948.1:g.11439C>T
NM_001301130.2:c.294-8060G>A
NM_001301131.2:c.293+10924G>A
NM_001363825.1:c.*38+5784G>A
NM_006941.4:c.470C>TMANE SELECT
NP_008872.1:p.Ala157Val
NP_008872.1:p.Ala157Val
LRG_271t1:c.470C>T
LRG_271:g.11439C>T
LRG_271p1:p.Ala157Val
NC_000022.10:g.38374101G>A
NM_006941.3:c.470C>T
P56693:p.Ala157Val

Protein change:

A157V; ALA157VAL

Links:

UniProtKB: P56693#VAR_066752; OMIM: 602229.0016; dbSNP: rs121909117

NCBI 1000 Genomes Browser:

rs121909117

Molecular consequence:

NM_001301130.2:c.294-8060G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001301131.2:c.293+10924G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001363825.1:c.*38+5784G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_006941.4:c.470C>T - 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
SCV002559345	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 4, 2022)	germline	clinical testing	Citation Link,
SCV004300012	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18348274, 34474183, 21898658, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002559345

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Feb 4, 2022)

germline

clinical testing

Citation Link,

SCV004300012

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A de novo missense mutation in the gene encoding the SOX10 transcription factor in a Spanish sporadic case of Waardenburg syndrome type IV.

Morín M, Viñuela A, Rivera T, Villamar M, Moreno-Pelayo MA, Moreno F, del Castillo I.

Am J Med Genet A. 2008 Apr 15;146A(8):1032-7. doi: 10.1002/ajmg.a.32181. No abstract available.

PubMed [citation]

PMID:: 18348274

Newborn screening with targeted sequencing: a multicenter investigation and a pilot clinical study in China.

Hao C, Guo R, Hu X, Qi Z, Guo Q, Liu X, Liu Y, Sun Y, Zhang X, Jin F, Wu X, Cai R, Zeng D, Hu X, Wang X, Ji X, Li W, Xing Q, Mu L, Jiang X, Yang X, Yang W, et al.

J Genet Genomics. 2022 Jan;49(1):13-19. doi: 10.1016/j.jgg.2021.08.008. Epub 2021 Aug 30.

PubMed [citation]

PMID:: 34474183

See all PubMed Citations (4)

Details of each submission

From GeneDx, SCV002559345.2

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

Description

Published functional studies demonstrate a damaging effect on DNA binding and protein localization (Chaoui A et al., 2011); 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: 18348274, 21898658, 30661772)

#	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, SCV004300012.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 157 of the SOX10 protein (p.Ala157Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Waardenburg syndrome (PMID: 18348274, 34474183). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 7408). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SOX10 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SOX10 function (PMID: 21898658). For these reasons, this variant has been classified as 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

Last Updated: Apr 20, 2024

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