SHH

sonic hedgehog signaling molecule, the group of Hedgehog signaling molecule family

Basic information

Region (hg38): 7:155799979-155812463

Previous symbols: [ "HPE3", "HLP3" ]

Links

ENSG00000164690 ∙ NCBI:6469 ∙ OMIM:600725 ∙ HGNC:10848 ∙ Uniprot:Q15465 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• polydactyly of a triphalangeal thumb (Definitive), mode of inheritance: AD
• microphthalmia, isolated, with coloboma 5 (Definitive), mode of inheritance: AD
• solitary median maxillary central incisor syndrome (Definitive), mode of inheritance: AD
• holoprosencephaly 3 (Definitive), mode of inheritance: AD
• microphthalmia, isolated, with coloboma 5 (Strong), mode of inheritance: AD
• holoprosencephaly (Supportive), mode of inheritance: AR
• triphalangeal thumb-polysyndactyly syndrome (Supportive), mode of inheritance: AD
• hypoplastic tibiae-postaxial polydactyly syndrome (Supportive), mode of inheritance: AD
• polydactyly of a triphalangeal thumb (Supportive), mode of inheritance: AD
• syndactyly type 4 (Supportive), mode of inheritance: AD
• microphthalmia, isolated, with coloboma (Supportive), mode of inheritance: AD
• autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome (Supportive), mode of inheritance: AD
• solitary median maxillary central incisor syndrome (Moderate), mode of inheritance: AD
• holoprosencephaly 3 (Definitive), mode of inheritance: AD
• skeletal system disorder (Moderate), mode of inheritance: AD
• holoprosencephaly 3 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Holoprosencephaly 3; Microphthalmia with coloboma 5	AD	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Craniofacial; Endocrine; Neurologic; Ophthalmologic	8896572; 10556296; 11471164; 11479728; 12567406; 12503095; 15221788; 19603532; 20531442; 21940735; 1976454; 20104608; 20301702; 22791840; 23112757
Variants in SHH have also been implicated in schizencephaly, but the data are unclear, and this may have co-occurred with typical holoprosencephaly-type malformations; Individuals with holoprosencephaly may demonstrate endocrine anomalies, including diabetes insipidus

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SHH gene.

• Holoprosencephaly 3 (136 variants)
• not provided (123 variants)
• Inborn genetic diseases (22 variants)
• not specified (13 variants)
• SHH-related condition (5 variants)
• Schizencephaly (4 variants)
• Solitary median maxillary central incisor syndrome (4 variants)
• Microphthalmia, isolated, with coloboma 5 (4 variants)
• 10 conditions (1 variants)
• Septo-optic dysplasia sequence (1 variants)
• Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (1 variants)
• SHH-Related Disorders (1 variants)
• Holoprosencephaly sequence (1 variants)
• Solitary median maxillary central incisor syndrome;Schizencephaly;Microphthalmia, isolated, with coloboma 5;Holoprosencephaly 3 (1 variants)
• Acrocallosal syndrome (1 variants)
• Microphthalmia, isolated, with coloboma 5;Holoprosencephaly 3;Solitary median maxillary central incisor syndrome;Schizencephaly (1 variants)
• Holoprosencephaly 3;Schizencephaly;Microphthalmia, isolated, with coloboma 5;Solitary median maxillary central incisor syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SHH gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	48	3	56
missense	3	8	110	6	1	128
nonsense	8	7				15
start loss						0
frameshift	6	2	2			10
inframe indel		2	7			9
splice donor/acceptor (+/-2bp)	1	1				2
splice region			1	4		5
non coding			3	11	12	26
Total	18	20	127	65	16

Highest pathogenic variant AF is 0.0000856

Variants in SHH

This is a list of pathogenic ClinVar variants found in the SHH region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
7-155800076-G-T		Partial agenesis of the corpus callosum	Pathogenic (May 13, 2021)
7-155800141-C-T			Benign (Dec 08, 2017)
7-155800142-G-A		SHH-related disorder	Likely benign (Nov 09, 2021)
7-155800159-A-G		SHH-related disorder	Likely benign (Jul 12, 2022)
7-155800163-G-A		SHH-related disorder	Likely benign (Mar 09, 2023)
7-155800178-C-T		SHH-related disorder	Likely benign (Aug 29, 2019)
7-155800179-G-A		SHH-related disorder	Likely benign (Jul 01, 2023)
7-155802688-A-G			Likely benign (Aug 15, 2020)
7-155802776-A-ATTATTC			Benign (Aug 08, 2019)
7-155802865-G-C			Likely benign (Aug 15, 2019)
7-155802871-T-C			Likely benign (Aug 23, 2019)
7-155802875-G-C			Likely benign (Aug 08, 2019)
7-155802889-G-GC			Uncertain significance (Apr 02, 2021)
7-155802892-C-A		SHH-related disorder	Conflicting classifications of pathogenicity (Nov 19, 2022)
7-155802895-C-T		SHH-related disorder	Likely benign (Mar 01, 2022)
7-155802918-CA-C			Uncertain significance (Apr 19, 2022)
7-155802924-C-T		Holoprosencephaly 3	Likely benign (Nov 23, 2022)
7-155802938-C-T		Holoprosencephaly 3	Uncertain significance (Nov 10, 2022)
7-155802949-A-G			Uncertain significance (Dec 05, 2022)
7-155802954-C-T			Likely pathogenic (Jan 01, 2022)
7-155802955-C-T		Holoprosencephaly 3	Uncertain significance (Apr 10, 2023)
7-155802958-G-A		Holoprosencephaly 3	Uncertain significance (Dec 02, 2021)
7-155802967-T-C		Holoprosencephaly 3	Uncertain significance (Jan 25, 2023)
7-155802980-G-A			Likely pathogenic (Feb 09, 2022)
7-155802982-G-T		Holoprosencephaly 3	Pathogenic/Likely pathogenic (Jun 15, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SHH	protein_coding	protein_coding	ENST00000297261	3	12288

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.983	0.0174	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.95	106	232	0.456	0.0000119	2873
Missense in Polyphen		29	110.06	0.26349		1320
Synonymous	-1.15	128	113	1.14	0.00000628	1027
Loss of Function	3.25	0	12.3	0.00	5.36e-7	147

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Sonic hedgehog protein: The C-terminal part of the sonic hedgehog protein precursor displays an autoproteolysis and a cholesterol transferase activity (By similarity). Both activities result in the cleavage of the full-length protein into two parts (ShhN and ShhC) followed by the covalent attachment of a cholesterol moiety to the C-terminal of the newly generated ShhN (By similarity). Both activities occur in the reticulum endoplasmic (By similarity). Once cleaved, ShhC is degraded in the endoplasmic reticulum (By similarity). {ECO:0000250|UniProtKB:Q62226}.
• Disease: DISEASE: Microphthalmia, isolated, with coloboma, 5 (MCOPCB5) [MIM:611638]: A disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues. Ocular abnormalities like opacities of the cornea and lens, scaring of the retina and choroid, and other abnormalities may also be present. Ocular colobomas are a set of malformations resulting from abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). {ECO:0000269|PubMed:12503095}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Holoprosencephaly 3 (HPE3) [MIM:142945]: A structural anomaly of the brain, in which the developing forebrain fails to correctly separate into right and left hemispheres. Holoprosencephaly is genetically heterogeneous and associated with several distinct facies and phenotypic variability. The majority of holoprosencephaly type 3 cases are apparently sporadic, although clear examples of autosomal dominant inheritance have been described. {ECO:0000269|PubMed:10441331, ECO:0000269|PubMed:10556296, ECO:0000269|PubMed:11479728, ECO:0000269|PubMed:15107988, ECO:0000269|PubMed:15221788, ECO:0000269|PubMed:15942952, ECO:0000269|PubMed:15942953, ECO:0000269|PubMed:16282375, ECO:0000269|PubMed:17001669, ECO:0000269|PubMed:19603532, ECO:0000269|PubMed:8896572, ECO:0000269|PubMed:9302262}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Solitary median maxillary central incisor (SMMCI) [MIM:147250]: Rare dental anomaly characterized by the congenital absence of one maxillary central incisor. {ECO:0000269|PubMed:11471164, ECO:0000269|PubMed:15103725}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Triphalangeal thumb-polysyndactyly syndrome (TPTPS) [MIM:174500]: Autosomal dominant syndrome. It is characterized by a wide spectrum of pre- and post-axial abnormalities due to altered SHH expression pattern during limb development. {ECO:0000269|PubMed:12837695, ECO:0000269|PubMed:18417549}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH expression.; DISEASE: Preaxial polydactyly 2 (PPD2) [MIM:174500]: Polydactyly consists of duplication of the distal phalanx. The thumb in PPD2 is usually opposable and possesses a normal metacarpal. {ECO:0000269|PubMed:12837695}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences (PubMed:12837695). {ECO:0000269|PubMed:12837695}.; DISEASE: Hypoplasia or aplasia of tibia with polydactyly (THYP) [MIM:188740]: An autosomal dominant disease characterized by hypoplastic or absent tibia, and polydactyly. {ECO:0000269|PubMed:19847792, ECO:0000269|PubMed:24965254}. Note=The gene represented in this entry is involved in disease pathogenesis. Mutations located in intron 5 of LMBR1 disrupt a long-range, cis-regulatory element of SHH and result in abnormal, ectopic SHH expression with pathological consequences. {ECO:0000303|PubMed:19847792, ECO:0000303|PubMed:24965254}.; DISEASE: Laurin-Sandrow syndrome (LSS) [MIM:135750]: A rare autosomal dominant disorder characterized by polysyndactyly of hands and/or feet, mirror image duplication of the feet, nasal defects, and loss of identity between fibula and tibia. Some patients do not have nasal abnormalities (segmental Laurin-Sandrow syndrome). {ECO:0000269|PubMed:24456159}. Note=The gene represented in this entry is involved in disease pathogenesis. Abnormal SHH limb expression with pathological consequences is caused by duplications (16-75 kb) involving the ZPA regulatory sequence (ZRS), a SHH long-range cis-regulatory element, located in LMBR1 intron 5 (PubMed:24456159).
• Pathway: Gastric cancer - Homo sapiens (human);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);HH-Core;Heart Development;Hair Follicle Development- Induction (Part 1 of 3);Differentiation Pathway;Dopaminergic Neurogenesis;Ectoderm Differentiation;Tgif disruption of Shh signaling;BMP Signaling Pathway in Eyelid Development;EDA Signalling in Hair Follicle Development;Hedgehog Signaling Pathway;Hedgehog Signaling Pathway;Signaling by GPCR;Disease;Signal Transduction;sonic hedgehog receptor ptc1 regulates cell cycle;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;Hedgehog;Release of Hh-Np from the secreting cell;Hedgehog ligand biogenesis;Class B/2 (Secretin family receptors);GPCR ligand binding;GPCR signaling-G alpha s Epac and ERK;Ligand-receptor interactions;GPCR signaling-G alpha s PKA and ERK;Hedgehog ,on, state;Signaling by Hedgehog;Validated transcriptional targets of TAp63 isoforms;FOXA1 transcription factor network;GPCR signaling-G alpha i;Hh mutants that don,t undergo autocatalytic processing are degraded by ERAD;Hh mutants abrogate ligand secretion;Glypican 3 network;Diseases of signal transduction;Hedgehog signaling events mediated by Gli proteins;Signaling events mediated by the Hedgehog family (Consensus)

Recessive Scores

• pRec: 0.891

Haploinsufficiency Scores

• pHI: 0.491
• hipred: Y
• hipred_score: 0.875
• ghis: 0.616

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: H
• gene_indispensability_pred: E
• gene_indispensability_score: 0.750

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Shh
• Phenotype: muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); taste/olfaction phenotype; endocrine/exocrine gland phenotype; digestive/alimentary phenotype; limbs/digits/tail phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; liver/biliary system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); reproductive system phenotype; normal phenotype

Zebrafish Information Network

• Gene name: shhb
• Affected structure: somite
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;branching involved in blood vessel morphogenesis;vasculogenesis;metanephros development;branching involved in ureteric bud morphogenesis;cell fate specification;neural crest cell migration;heart looping;positive regulation of neuroblast proliferation;osteoblast development;lymphoid progenitor cell differentiation;determination of left/right asymmetry in lateral mesoderm;endocytosis;smoothened signaling pathway;positive regulation of hh target transcription factor activity;cell-cell signaling;pattern specification process;ectoderm development;neuroblast proliferation;axon guidance;central nervous system development;ventral midline development;hindgut morphogenesis;heart development;blood coagulation;androgen metabolic process;positive regulation of cell population proliferation;embryonic pattern specification;polarity specification of anterior/posterior axis;dorsal/ventral pattern formation;regulation of signaling receptor activity;oligodendrocyte development;striated muscle tissue development;positive regulation of skeletal muscle cell proliferation;myotube differentiation;intein-mediated protein splicing;spinal cord dorsal/ventral patterning;spinal cord motor neuron differentiation;thalamus development;dorsal/ventral neural tube patterning;cerebellar granule cell precursor proliferation;smoothened signaling pathway involved in regulation of cerebellar granule cell precursor cell proliferation;telencephalon regionalization;establishment of cell polarity;regulation of proteolysis;positive regulation of Wnt signaling pathway;lung development;embryonic limb morphogenesis;negative regulation of cell migration;male genitalia development;prostate gland development;thyroid gland development;forebrain development;midbrain development;hindbrain development;pancreas development;hair follicle morphogenesis;negative regulation of proteasomal ubiquitin-dependent protein catabolic process;T cell differentiation in thymus;positive regulation of T cell differentiation in thymus;positive regulation of immature T cell proliferation in thymus;negative regulation of transcription elongation from RNA polymerase II promoter;protein localization to nucleus;embryonic forelimb morphogenesis;embryonic hindlimb morphogenesis;regulation of cell population proliferation;negative regulation of T cell proliferation;positive regulation of protein import into nucleus;odontogenesis of dentin-containing tooth;regulation of odontogenesis;embryonic digit morphogenesis;camera-type eye development;negative regulation of apoptotic process;CD4-positive or CD8-positive, alpha-beta T cell lineage commitment;positive thymic T cell selection;negative thymic T cell selection;intermediate filament organization;myoblast differentiation;negative regulation of cell differentiation;positive regulation of smoothened signaling pathway;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of alpha-beta T cell differentiation;negative regulation of alpha-beta T cell differentiation;cell development;thymus development;embryonic digestive tract morphogenesis;embryonic foregut morphogenesis;positive regulation of skeletal muscle tissue development;animal organ formation;neuron fate commitment;embryonic skeletal system development;positive regulation of oligodendrocyte differentiation;branching morphogenesis of an epithelial tube;inner ear development;formation of anatomical boundary;stem cell development;positive regulation of striated muscle cell differentiation;positive regulation of cell division;Bergmann glial cell differentiation;roof of mouth development;canonical Wnt signaling pathway;limb bud formation;lung epithelium development;trachea morphogenesis;branching involved in salivary gland morphogenesis;bud outgrowth involved in lung branching;right lung development;left lung development;lung lobe morphogenesis;lung-associated mesenchyme development;primary prostatic bud elongation;prostate epithelial cord elongation;salivary gland cavitation;epithelial cell proliferation involved in salivary gland morphogenesis;regulation of prostatic bud formation;epithelial-mesenchymal signaling involved in prostate gland development;positive regulation of epithelial cell proliferation involved in prostate gland development;regulation of mesenchymal cell proliferation involved in prostate gland development;mesenchymal smoothened signaling pathway involved in prostate gland development;artery development;mesenchymal cell proliferation involved in lung development;somite development;positive regulation of sclerotome development;cellular response to lithium ion;dopaminergic neuron differentiation;renal system development;metanephric mesenchymal cell proliferation involved in metanephros development;negative regulation of canonical Wnt signaling pathway;negative regulation of cholesterol efflux;apoptotic signaling pathway;regulation of nodal signaling pathway involved in determination of lateral mesoderm left/right asymmetry;regulation of protein localization to nucleus;negative regulation of dopaminergic neuron differentiation;tracheoesophageal septum formation;negative regulation of ureter smooth muscle cell differentiation;positive regulation of ureter smooth muscle cell differentiation;negative regulation of kidney smooth muscle cell differentiation;positive regulation of kidney smooth muscle cell differentiation;positive regulation of mesenchymal cell proliferation involved in ureter development;negative regulation of mesenchymal cell apoptotic process
• Cellular component: extracellular region;extracellular space;endoplasmic reticulum lumen;cytosol;plasma membrane;cell surface;membrane raft;collagen-containing extracellular matrix
• Molecular function: endopeptidase activity;patched binding;calcium ion binding;protein binding;glycosaminoglycan binding;zinc ion binding;morphogen activity;laminin-1 binding