17-72124177-C-G

Variant names:

• chr17-72124177-C-G
• rs80338688
• NM_000346.4:c.1320C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000346.4(SOX9):​c.1320C>G​(p.Tyr440*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y440Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOX9 NM_000346.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: -0.0730
• Publications: 15 publications found

Genes affected

SOX9 (HGNC:11204): (SRY-box transcription factor 9) The protein encoded by this gene recognizes the sequence CCTTGAG along with other members of the HMG-box class DNA-binding proteins. It acts during chondrocyte differentiation and, with steroidogenic factor 1, regulates transcription of the anti-Muellerian hormone (AMH) gene. Deficiencies lead to the skeletal malformation syndrome campomelic dysplasia, frequently with sex reversal. [provided by RefSeq, Jul 2008]

SOX9-AS1 (HGNC:49321): (SOX9 antisense RNA 1)

ENSG00000288605 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-72124177-C-G is Pathogenic according to our data. Variant chr17-72124177-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOX9	NM_000346.4	c.1320C>G	p.Tyr440*	stop_gained	Exon 3 of 3	ENST00000245479.3	NP_000337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOX9	ENST00000245479.3	c.1320C>G	p.Tyr440*	stop_gained	Exon 3 of 3	1	NM_000346.4	ENSP00000245479.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Apr 30, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation, as the last 70 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27065010, 9002675, 15806394, 36343245, 36584300, 34627339, 8001137) -

Nov 30, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SOX9 c.1320C>G; p.Tyr440Ter variant (rs80338688) is reported in the literature in individuals affected with campomelic dysplasia or suspected skeletal dysplasia (Hageman 1998, Meyer 1997, Pop 2005, Scocchia 2021), including an apparently de novo variant in one individual (Wagner 1994). This variant is also reported in ClinVar (Variation ID: 2510). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Additionally, another variant at this nucleotide resulting in the same premature termination codon (c.1320C>A; p.Tyr440Ter) has been reported in individuals with campomelic dysplasia and is considered pathogenic (Pop 2005). Functional analyses of the variant protein demonstrate reduced but not eliminated transactivation activity (Au 2023, Pop 2005, Wagner 1994), suggesting this may be a hypomorphic variant with potential combined haploinsufficient and dominant-negative mechanisms. This variant results in a premature termination codon in the last exon of the SOX9 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein. Based on available information, this variant is considered to be pathogenic. References: Au TYK et al. Hypomorphic and dominant-negative impact of truncated SOX9 dysregulates Hedgehog-Wnt signaling, causing campomelia. Proc Natl Acad Sci U S A. 2023 Jan 3;120(1):e2208623119. PMID: 36584300. Hageman RM et al. Mutation analysis of the SOX9 gene in a patient with campomelic dysplasia. Hum Mutat. 1998;Suppl 1:S112-3. PMID: 9452058. Meyer J et al. Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations. Hum Mol Genet. 1997 Jan;6(1):91-8. PMID: 9002675. Pop R et al. A homozygous nonsense mutation in SOX9 in the dominant disorder campomelic dysplasia: a case of mitotic gene conversion. Hum Genet. 2005 Jun;117(1):43-53. PMID: 15806394. Scocchia A et al. Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia. Orphanet J Rare Dis. 2021 Oct 9;16(1):412. PMID: 34627339. Wagner T et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell. 1994 Dec 16;79(6):1111-20. PMID: 8001137. -

CAMPOMELIC DYSPLASIA WITH AUTOSOMAL SEX REVERSAL Pathogenic:1

Jun 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Connective tissue disorder Pathogenic:1

Mar 01, 2020

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Camptomelic dysplasia Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.30
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.52	D
PhyloP100		-0.073
Vest4		0.92
GERP RS		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs80338688; hg19: chr17-70120318;