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Fetal anomalies

Gene: SOX3

Amber List (moderate evidence)

SOX3 (SRY-box 3)
EnsemblGeneIds (GRCh38): ENSG00000134595
EnsemblGeneIds (GRCh37): ENSG00000134595
OMIM: 313430, Gene2Phenotype
SOX3 is in 10 panels

3 reviews

Seb Lunke (Victorian Clinical Genetics Services)

Comment on mode of pathogenicity: Mouse model demonstrates that mechanism of disease is polyAlanine tract leading to a loss of function of the protein
Created: 24 Feb 2022, 3:04 a.m. | Last Modified: 24 Feb 2022, 3:04 a.m.
Panel Version: 0.4137
Comment on list classification: Ala Repeat expansion linked to growth hormone deficiency, but not much evidence so far, onset appears post-natal, and described brain MRI findings appear subtle.
Created: 24 Feb 2022, 3:03 a.m. | Last Modified: 24 Feb 2022, 3:03 a.m.
Panel Version: 0.4136

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

I don't know

Most of the evidence for gene-disease association comes from reports of duplications and deletions of Xq26-27 including SOX3 (Xq27.1). Reports of pathogenic SNVs are rare, and note ID is described as 'mild'. Also note some evidence of polyA expansion being linked to the ID phenotype; conflicting evidence regarding the polyA deletion.
Created: 14 Feb 2020, 9:03 p.m. | Last Modified: 14 Feb 2020, 9:03 p.m.
Panel Version: 0.2181

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mental retardation, X-linked, with isolated growth hormone deficiency, MIM# 300123

Chern Lim (Victorian Clinical Genetics Services)

I don't know

- Two disease-associated missense variants reported:
1) p.(Ser150Tyr) in a family with 3 affected hemizygous males with mild intellectual disability, hypopituitarism etc, female carriers were unaffected (PMID:29175558);
2) p.(Pro142Thr) in a male twin-pair with X-linked hypopituitarism with mild learning difficulties. Luciferase study showed increased transcriptional activation. In vitro study showed impaired repression of B-catenin-mediated transcription. (PMID:30125608)

- Two poly-alanine expansions reported as pathogenic in ClinVar:
1) p.(Ala243_249ins11Ala) in a male patient with X-linked intellectual disability and isolated growth hormone deficiency. (PMID:12428212)
2) p.(Ala240_241ins7Ala) in a family with male siblings with panhypopituitarism. Luciferase study showed reduced activation efficacy by SOX3 due to the expansion. (PMID:15800844)

- Study in mice showed poly-Ala expansion in Sox3 resulted in reduced SOX3 protein levels in the cell nucleus (PMID:23505376).

- Poly-Ala deletion (p.A243_A248del6, del6PA) was reported in a female patient with hypopituitarism, luciferase assay showed increased transcriptional activation, possibly increasing activation of SOX3 target genes (PMID:21289259). However in gnomAD, poly-Ala deletion in that region is common in hemizygotes, but duplications are not common.
Created: 14 Feb 2020, 4:17 a.m. | Last Modified: 14 Feb 2020, 4:17 a.m.
Panel Version: 0.2178

Mode of inheritance
X-LINKED: hemizygous mutation in males, biallelic mutations in females

Phenotypes
Mental retardation, X-linked, with isolated growth hormone deficiency, MIM#300123; Panhypopituitarism, X-linked, MIM#312000

Publications

Mode of pathogenicity
Other

Details

Mode of Inheritance
X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Sources
  • Expert Review Amber
  • Genomics England PanelApp
  • Genetic Health Queensland
Phenotypes
  • Panhypopituitarism, X-linked, OMIM:312000
  • Panhypopituitarism, X-linked, MONDO:0010712
  • Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252
  • Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123
Tags
SV/CNV
OMIM
313430
Clinvar variants
Variants in SOX3
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

24 Feb 2022, Gel status: 2

Added Tag

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Tag SV/CNV tag was added to gene: SOX3.

24 Feb 2022, Gel status: 2

Entity classified by Genomics England curator

Seb Lunke (Victorian Clinical Genetics Services)

Gene: sox3 has been classified as Amber List (Moderate Evidence).

24 Feb 2022, Gel status: 2

Set publications

Seb Lunke (Victorian Clinical Genetics Services)

Publications for gene: SOX3 were set to

24 Feb 2022, Gel status: 2

Set mode of pathogenicity

Seb Lunke (Victorian Clinical Genetics Services)

Mode of pathogenicity for gene: SOX3 was changed from to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

24 Feb 2022, Gel status: 2

Entity classified by Genomics England curator

Seb Lunke (Victorian Clinical Genetics Services)

Gene: sox3 has been classified as Amber List (Moderate Evidence).

24 Oct 2021, Gel status: 3

Created, Added New Source, Set mode of inheritance, Set Phenotypes

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

gene: SOX3 was added gene: SOX3 was added to Fetal anomalies. Sources: Expert Review Green,Genomics England PanelApp Mode of inheritance for gene: SOX3 was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males) Phenotypes for gene: SOX3 were set to Panhypopituitarism, X-linked, OMIM:312000; Panhypopituitarism, X-linked, MONDO:0010712; Intellectual disability, X-linked, with panhypopituitarism, MONDO:0010252; Mental retardation, X-linked, with isolated growth hormone deficiency, OMIM:300123