SOST

protein-coding

sclerostin, the group of DAN family

Gene summary

Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative in neuroblastoma) family of bone morphogenetic protein (BMP) antagonists. Loss-of-function mutations in this gene are associated with an autosomal-recessive disorder, sclerosteosis, which causes progressive bone overgrowth. A deletion downstream of this gene, which causes reduced sclerostin expression, is associated with a milder form of the disorder called van Buchem disease. [provided by RefSeq, Jul 2008]

MANE transcript

NM_025237.3

Inheritance

AR, AD

ClinVar variants

P:8U:49B:22

Top phenotype

Craniodiaphyseal dysplasia, autosomal dominant; Sclerosteosis 1; van Buchem disease

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:43,753,738-43,758,791

External References & Databases

Ensembl (ENSG00000167941)

Transcript & Mutation Effects

hg38 • Region Span ~5.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sclerosteosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017838

Submitter: Orphanet

craniodiaphyseal dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009031

Submitter: Orphanet

craniodiaphyseal dysplasia, autosomal dominantLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0021021

Submitter: Labcorp Genetics (formerly Invitae)

sclerosteosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010016

Submitter: Labcorp Genetics (formerly Invitae)

sclerosteosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010016

Submitter: PanelApp Australia

hyperostosis corticalis generalisataSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009395

Submitter: Orphanet

sclerosteosis 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010016

Submitter: Genomics England PanelApp

craniodiaphyseal dysplasia, autosomal dominantLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0021021

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Craniodiaphyseal dysplasia, autosomal dominant; Sclerosteosis 1; van Buchem diseaseAD/AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Musculoskeletal

Intervention: Musculoskeletal

Rationale: Starting in infancy, regular surveillance for sequelae related to overgrowth, including hearing evaluation, assessment of signs of increased intracranial pressure and cranial nerve entrapment, can allow early surgical management

Refs: 13924477; 3276528; 6323069; 8433139; 9712543; 9463328; 11179006; 11836356; 12116252; 12694228; 14671168; 17245025; 17853455; 20301406; 20583295; 21221996

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SOST variants in ClinVar

6 Conditions Cataloged

not providedTotal: 31

Inborn genetic diseasesTotal: 26

Sclerosteosis 1Total: 25

SOST-related disorderTotal: 8

not specifiedTotal: 7

Craniodiaphyseal dysplasia, autosomal dominantTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_025237.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			3 clinvar	19 clinvar		22
missense	1 clinvar	1 clinvar	41 clinvar	2 clinvar	1 clinvar	46
nonsense	3 clinvar	1 clinvar	3 clinvar			7
start loss						0
frameshift	1 clinvar	1 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	5	3	49	21	1	79

Highest pathogenic variant AF is 0.00001486987

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_025237.3	RefSeq	NP_079513.1	2	MANE Select
ENST00000301691.3	Ensembl	ENSP00000301691.1	2	MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Wnt signaling pathway - Homo sapiens (human)
Role of Osx and miRNAs in tooth development
Wnt Signaling Pathway
Signaling by WNT
Signal Transduction

Biological Process

ossification
response to mechanical stimulus
Wnt signaling pathway
negative regulation of ossification
negative regulation of BMP signaling pathway

Molecular Function

protein binding
transcription factor binding
heparin binding

Cellular Component

extracellular region
extracellular space
Golgi apparatus
protein-containing complex
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301691
Coding exons: 2
Length: 5058
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 3
Defined: 125747
p: 0.0000119

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.835	106	133	0.796	0.00000745	1331
Missense (PolyPhen)		34	44.002	0.77269		426
Synonymous	0.0468	62	62.5	0.992	0.00000378	453
Loss of Function	2.38	0	6.60	0.00	2.84e-7	71

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000019	0.000018	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Negative regulator of bone growth that acts through inhibition of Wnt signaling and bone formation. {ECO:0000269|PubMed:15908424}.;
Disease: DISEASE: Van Buchem disease (VBCH) [MIM:239100]: VBCH is an autosomal recessive sclerosing bone dysplasia characterized by endosteal hyperostosis of the mandible, skull, ribs, clavicles, and diaphyses of the long bones. Affected patients present a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet. The clinical consequence of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurological pain, and, very rarely, blindness as a consequence of optic atrophy. Serum alkaline phosphatase levels are elevated. {ECO:0000269|PubMed:11836356}. Note=The disease is caused by mutations affecting the gene represented in this entry. A 52 kb deletion downstream of SOST results in SOST transcription suppression causing van Buchem disease.; DISEASE: Craniodiaphyseal dysplasia autosomal dominant (CDD) [MIM:122860]: A severe bone dysplasia characterized by massive generalized hyperostosis and sclerosis, especially involving the skull and facial bones. The sclerosis is so severe that the resulting facial distortion is referred to as 'leontiasis ossea' (leonine faces) and the bone deposition results in progressive stenosis of craniofacial foramina. Respiratory obstruction due to choanal stenosis compromises the clinical outcomes of affected patients. {ECO:0000269|PubMed:21221996}. Note=The disease is caused by mutations affecting the gene represented in this entry. Heterozygous mutations located in the secretion signal of the SOST gene prevent sclerostin secretion and can be responsible for craniodiaphyseal dysplasia.;

Recessive Scores

pRec: 0.405

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.283

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium