NM_000346.4(SOX9):c.508C>G (p.Pro170Ala) AND Camptomelic dysplasia

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jun 20, 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:: RCV001329809.13

Allele description [Variation Report for NM_000346.4(SOX9):c.508C>G (p.Pro170Ala)]

NM_000346.4(SOX9):c.508C>G (p.Pro170Ala)

Gene:

SOX9:SRY-box transcription factor 9 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q24.3

Genomic location:

Preferred name:

NM_000346.4(SOX9):c.508C>G (p.Pro170Ala)

HGVS:

NC_000017.11:g.72122795C>G
NG_012490.1:g.6776C>G
NM_000346.4:c.508C>GMANE SELECT
NP_000337.1:p.Pro170Ala
NC_000017.10:g.70118936C>G
NM_000346.3:c.508C>G

Protein change:

P170A

Links:

dbSNP: rs866706988

NCBI 1000 Genomes Browser:

rs866706988

Molecular consequence:

NM_000346.4:c.508C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Camptomelic dysplasia (CMPD)
Synonyms:: CMPD1/SRA1; Campomelic Dysplasia
Identifiers:: MONDO: MONDO:0007251; MedGen: C1861922; Orphanet: 140; OMIM: 114290

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001521346	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001739384	Institute of Human Genetics, Heidelberg University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002259073	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 20, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9002675, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001521346

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001739384

Institute of Human Genetics, Heidelberg University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 21, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002259073

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 20, 2022)

germline

clinical testing

PubMed (2)
[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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations.

Meyer J, Südbeck P, Held M, Wagner T, Schmitz ML, Bricarelli FD, Eggermont E, Friedrich U, Haas OA, Kobelt A, Leroy JG, Van Maldergem L, Michel E, Mitulla B, Pfeiffer RA, Schinzel A, Schmidt H, Scherer G.

Hum Mol Genet. 1997 Jan;6(1):91-8.

PubMed [citation]

PMID:: 9002675

See all PubMed Citations (3)

Details of each submission

From Baylor Genetics, SCV001521346.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Heidelberg University, SCV001739384.2

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

Description

The variant was not found in DNA extracted from the parents' blood samples (PS2), the variant is absent from controls (gnomAD; PM2), multiple lines of computational evidence support a deleterious effect (PP3) and it is localized at an amino acid site where different missense changes determined to be pathogenic have been seen before (PM5); therefore we classified it as pathogenic according to ACMG criteria.

#	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, SCV002259073.4

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

Description

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 170 of the SOX9 protein (p.Pro170Ala). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Pro170 amino acid residue in SOX9. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9002675). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 SOX9 protein function. ClinVar contains an entry for this variant (Variation ID: 996802). This variant has not been reported in the literature in individuals affected with SOX9-related conditions. This variant is not present in population databases (gnomAD no frequency).

#	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 13, 2025

ClinVar

Relating variation to medicine