SMO

protein-coding

smoothened, frizzled class receptor, the group of G protein-coupled receptors, Class F frizzled

Gene summary

The protein encoded by this gene is a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. The encoded protein tranduces signals to other proteins after activation by a hedgehog protein/patched protein complex. [provided by RefSeq, Jul 2010]

Previous symbols:

SMOH

MANE transcript

NM_005631.5

Inheritance

AR, AD

ClinVar variants

P:11U:145B:38

Top phenotype

Pallister-Hall like syndrome

gnomAD constraint

pLI —, LoF o/e 0.46

Max pathogenic AF

—

Genomic locus

chr7:129,188,633-129,213,545

External References & Databases

Ensembl (ENSG00000128602)

Transcript & Mutation Effects

hg38 • Region Span ~24.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital hypothalamic hamartoma syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009436

Submitter: Ambry Genetics

Curry-Jones syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011134

Submitter: G2P

Hirschsprung diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018309

Submitter: Orphanet

medulloblastomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: Ambry Genetics

Curry-Jones syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011134

Submitter: PanelApp Australia

mosaic SMO syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1030005

Submitter: ClinGen

The smoothened frizzled class receptor is encoded by the *SMO *gene and is located at 7q32.1. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in molecular mechanism, phenotypic spectrum, and mode of inheritance. Therefore, Curry-Jones syndrome, somatic mosaic (MIM:601707) and Happle-Tinschert Syndrome were lumped, while Pallister-Hall-like syndrome (OMIM:241800) was split. Mosaic SMO syndrome is caused by a postzygotic mutation (c.1234 C>T p.Leu412Phe) in the *SMO *gene. The altered amino acid, Leu412, localizes to transmembrane helix 5 of *SMO* within one of three pivot regions that are likely to have a key role in the conformational changes required for receptor activation (PMID 27236920). This mutant allele is present at levels below 50% in samples and is not reliably detected in blood or saliva (PMID 27236920). This gene-disease relationship was first described in 2016 (PMID 27236920 Twigg et al., 2016). Sixteen probands reported in six publications were included in this curation (PMIDs: 27236920, 31825089, 31607746, 29335739, 31120550, 36707059). This gene-disease relationship is also supported by biochemical assays, functional alteration, expression, and non-human model organisms (PMIDs: 12192414, 15618519, 21859383, 24859340, 15520185, 15107405). In summary, there is definitive evidence supporting the relationship between *SMO* and mosaic SMO syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings. This classification was approved by the Craniofacial Malformations Gene Curation Expert Panel on the meeting date 11/16/2023 (SOP Version 9).

congenital hypothalamic hamartoma syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009436

Submitter: Ambry Genetics

congenital hypothalamic hamartoma syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009436

Submitter: PanelApp Australia

congenital hypothalamic hamartoma syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009436

Submitter: ClinGen

The SMO gene is located on chromosome 7 at 7q32.1 and encodes a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. SMO was first reported in relation to autosomal recessive Pallister-Hall-like syndrome in 2018 by Rubino et al. (PMID: 30497210). Pallister-Hall-like syndrome is a pleiotropic disorder characterized by postaxial polydactyly, hypothalamic hamartoma, cardiac and skeletal anomalies, craniofacial dysmorphisms, and language delay. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the ClinGen Craniofacial Malformations GCEP found differences in inheritance pattern and phenotypic variability between the disease assertions. Therefore, the following disease entities have been split into multiple disease entities, Curry-Jones syndrome (OMIM:601707) and Pallister-Hall-like syndrome (OMIM:241800). The split curation for Curry-Jones syndrome has been curated separately by the Craniofacial Malformations GCEP. Here, the Syndromic Disorders GCEP has curated the relationship between SMO and Pallister-Hall-like syndrome. Seven variants (5 missense, 1 nonsense, and 1 splicing variants) that have been reported in five probands in two publications (PMIDs: 32413283, 35034092) are included in this curation. This gene-disease relationship is also supported by expression, protein-protein interactions, biochemical function, and animal model evidence (PMIDs: 29558958, 11440720, 27801979, 29571613, 32413283). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date October 20th, 2023 (SOP Version 10).

congenital hypothalamic hamartoma syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009436

Submitter: G2P

Clinical Genomic Database (CGD)

Pallister-Hall like syndromeAR

Manifestation: Cardiovascular; Endocrine; Musculoskeletal; Neurologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management; Interventions related to endocrine abnormalities may be beneficial; Surgical interventions related to hypothalamic hamartoma may be indicated

Comments: Somatic variants can result in Curry-Jones syndrome

Refs: 27236920; 30497210; 32413283

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SMO variants in ClinVar

11 Conditions Cataloged

Inborn genetic diseasesTotal: 84

not providedTotal: 78

not specifiedTotal: 31

Congenital hypothalamic hamartoma syndromeTotal: 30

SMO-related disorderTotal: 15

Curry-Jones syndromeTotal: 9

Basal cell carcinoma, susceptibility to, 1Total: 3

Basal cell carcinoma, somaticTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005631.5. 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			7 clinvar	25 clinvar	2 clinvar	34
missense	6 clinvar	3 clinvar	134 clinvar	9 clinvar	2 clinvar	154
nonsense	1 clinvar		1 clinvar			2
start loss						0
frameshift		1 clinvar	3 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	7	4	145	34	4	194

Highest pathogenic variant AF is 0.000026651196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005631.5	RefSeq	NP_005622.1	12	MANE Select
ENST00000249373.8	Ensembl	ENSP00000249373.3	12	MANE Select
ENST00000462420.2	Ensembl	ENSP00000418720.2	4	Standard
ENST00000475779.1	Ensembl	ENSP00000420749.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
smo	Danio rerio	Structure: retinal ganglion cell Quality: process quality abnormal

Gene / Model

Organism

Observed Phenotype

smo

Danio rerio

Structure: retinal ganglion cell

Quality: process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Axon guidance - Homo sapiens (human)
Basal cell carcinoma - Homo sapiens (human)
Proteoglycans in cancer - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Hedgehog signaling pathway - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
vasculogenesis
osteoblast differentiation
in utero embryonic development
cell fate specification

Molecular Function

G protein-coupled receptor activity
patched binding
protein binding
drug binding

Cellular Component

Golgi apparatus
plasma membrane
caveola
cilium
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000249373
Coding exons: 12
Length: 24674
Individuals with no LoFs: 125711
Homozygous LoFs: 0
Heterozygous LoFs: 37
Defined: 125748
p: 0.000147

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.90	345	459	0.751	0.0000287	5019
Missense (PolyPhen)		78	130.22	0.59899		1386
Synonymous	0.0952	183	185	0.991	0.0000115	1657
Loss of Function	3.08	17	37.3	0.456	0.00000223	344

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: G protein-coupled receptor that probably associates with the patched protein (PTCH) to transduce the hedgehog's proteins signal. Binding of sonic hedgehog (SHH) to its receptor patched is thought to prevent normal inhibition by patched of smoothened (SMO). Required for the accumulation of KIF7, GLI2 and GLI3 in the cilia (PubMed:19592253). Interacts with DLG5 at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation (By similarity). {ECO:0000250|UniProtKB:P56726, ECO:0000269|PubMed:19592253}.;
Disease: DISEASE: Curry-Jones syndrome (CRJS) [MIM:601707]: A multisystem disorder characterized by patchy skin lesions, polysyndactyly, diverse cerebral malformations, unicoronal craniosynostosis, iris colobomas, microphthalmia, and intestinal malrotation with myofibromas or hamartomas. {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}. Note=The disease is caused by mutations affecting the gene represented in this entry. 8 individuals have been identified with the disease-causing mutation Phe-412 and all were mosaic. The mutation could not be reliably detected in blood, greatest success rates were obtained with affected tissues obtained by invasive procedures. It is thought that the mutation has arisen postzygotically early during embryonic development (PubMed:27236920). This mutation has also been identified in ameloblastoma, medulloblastoma, meningioma, and basal cell carcinoma, and has been reported as the oncogenic driver in some of these tumors (PubMed:24859340). {ECO:0000269|PubMed:24859340, ECO:0000269|PubMed:27236920}.;

Recessive Scores

pRec: 0.412

Intolerance Scores

LoFtool: 0.242
RVIS EVS: -0.57
RVIS percentile EVS: 18.9

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.963

Gene Damage Prediction

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