NM_006941.4(SOX10):c.323T>C (p.Met108Thr) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 13, 2022
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:: RCV002245947.12

Allele description [Variation Report for NM_006941.4(SOX10):c.323T>C (p.Met108Thr)]

NM_006941.4(SOX10):c.323T>C (p.Met108Thr)

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.323T>C (p.Met108Thr)

HGVS:

NC_000022.11:g.37983462A>G
NG_007948.1:g.6071T>C
NG_148296.1:g.739A>G
NM_001301130.2:c.294-2692A>G
NM_001301131.2:c.293+16292A>G
NM_001363825.1:c.*38+11152A>G
NM_006941.4:c.323T>CMANE SELECT
NP_008872.1:p.Met108Thr
NP_008872.1:p.Met108Thr
LRG_271t1:c.323T>C
LRG_271:g.6071T>C
LRG_271p1:p.Met108Thr
NC_000022.10:g.38379469A>G
NM_006941.3:c.323T>C

Protein change:

M108T

Links:

dbSNP: rs1932464492

NCBI 1000 Genomes Browser:

rs1932464492

Molecular consequence:

NM_001301130.2:c.294-2692A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001301131.2:c.293+16292A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001363825.1:c.*38+11152A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_006941.4:c.323T>C - 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
SCV002513662	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (May 12, 2022)	germline	clinical testing	Citation Link,
SCV004300013	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 13, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23643381, 34142234, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002513662

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(May 12, 2022)

germline

clinical testing

Citation Link,

SCV004300013

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 13, 2022)

germline

clinical testing

PubMed (3)
[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

Loss-of-function mutations in SOX10 cause Kallmann syndrome with deafness.

Pingault V, Bodereau V, Baral V, Marcos S, Watanabe Y, Chaoui A, Fouveaut C, Leroy C, Vérier-Mine O, Francannet C, Dupin-Deguine D, Archambeaud F, Kurtz FJ, Young J, Bertherat J, Marlin S, Goossens M, Hardelin JP, Dodé C, Bondurand N.

Am J Hum Genet. 2013 May 2;92(5):707-24. doi: 10.1016/j.ajhg.2013.03.024.

PubMed [citation]

PMID:: 23643381
PMCID:: PMC3644631

Analysis of genotype-phenotype relationships in 90 Chinese probands with Waardenburg syndrome.

Wang G, Li X, Gao X, Su Y, Han M, Gao B, Guo C, Kang D, Huang S, Yuan Y, Dai P.

Hum Genet. 2022 Apr;141(3-4):839-852. doi: 10.1007/s00439-021-02301-3. Epub 2021 Jun 17.

PubMed [citation]

PMID:: 34142234

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV002513662.2

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

Description

Identified in individuals with Kallmann Syndrome, but additional evidence is needed to support association with disease (Pingault et al., 2103; Maione et al., 2016); Published functional studies suggest this variant results in impairment of protein function, however additional studies are needed to validate the functional effect of this variant (Pingault et al., 2013); 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: 23643381, 27616149, 32442410, 33442024)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004300013.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 108 of the SOX10 protein (p.Met108Thr). This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects SOX10 function (PMID: 23643381). 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. ClinVar contains an entry for this variant (Variation ID: 995929). This missense change has been observed in individuals with Kallman syndrome and/or Waardenburg syndrome (PMID: 23643381, 34142234).

#	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: Nov 3, 2024

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