GDF6

growth differentiation factor 6, the group of Transforming growth factor beta superfamily

Basic information

Region (hg38): 8:96142332-96160806

Previous symbols: [ "SGM1" ]

Links

ENSG00000156466 ∙ NCBI:392255 ∙ OMIM:601147 ∙ HGNC:4221 ∙ Uniprot:Q6KF10 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Klippel-Feil syndrome 1, autosomal dominant (Definitive), mode of inheritance: AD
• Leber congenital amaurosis (Supportive), mode of inheritance: AD
• isolated Klippel-Feil syndrome (Supportive), mode of inheritance: AD
• Klippel-Feil syndrome 1, autosomal dominant (Limited), mode of inheritance: AD
• Leber congenital amaurosis 17 (Limited), mode of inheritance: Unknown
• isolated microphthalmia 4 (Limited), mode of inheritance: AD
• multiple synostoses syndrome 4 (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Deafness, autosomal recessive 118, with cochlear aplasia	AD/AR/Digenic	General	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Musculoskeletal; Ophthalmologic	8533765; 17236135; 18425797; 19129173; 19864492; 21070663; 23307924; 26643732; 29130651; 32369452
Deafness, autosomal recessive 118, with cochlear aplasia is due to variants in a downstream regulatory element affecting GDF6 expression; Digenic inheritance (with GDF3) has been reported

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDF6 gene.

• Klippel-Feil syndrome 1, autosomal dominant (85 variants)
• not provided (34 variants)
• Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4;Leber congenital amaurosis 17 (24 variants)
• Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4 (21 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4;Leber congenital amaurosis 17 (18 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4;Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6 (18 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17 (17 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17;Isolated microphthalmia 4 (16 variants)
• Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17 (14 variants)
• Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17;Isolated microphthalmia 4 (13 variants)
• Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4 (12 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4 (12 variants)
• Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17;Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant (12 variants)
• Klippel-Feil syndrome (11 variants)
• Leber congenital amaurosis 17;Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6 (10 variants)
• Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17 (10 variants)
• Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6;Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant (10 variants)
• Inborn genetic diseases (9 variants)
• Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17 (9 variants)
• Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4 (9 variants)
• Isolated microphthalmia 4;Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant;Microphthalmia, isolated, with coloboma 6 (8 variants)
• not specified (7 variants)
• Leber congenital amaurosis 17;Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant (7 variants)
• Isolated microphthalmia 4;Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6;Klippel-Feil syndrome 1, autosomal dominant (6 variants)
• Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6 (5 variants)
• Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6 (5 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Leber congenital amaurosis 17;Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6 (5 variants)
• Leber congenital amaurosis 17 (4 variants)
• Leber congenital amaurosis 17;Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4;Klippel-Feil syndrome 1, autosomal dominant (3 variants)
• Isolated microphthalmia 4 (3 variants)
• Multiple synostoses syndrome 4 (2 variants)
• Microphthalmia, isolated, with coloboma 6;Isolated microphthalmia 4;Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant (2 variants)
• Congenital anomaly of kidney and urinary tract (2 variants)
• Leber congenital amaurosis 17;Klippel-Feil syndrome 1, autosomal dominant;Isolated microphthalmia 4;Microphthalmia, isolated, with coloboma 6;Multiple synostoses syndrome 4 (1 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Autosomal dominant Parkinson disease 8 (1 variants)
• Microphthalmia, isolated, with coloboma 6 (1 variants)
• Klippel-Feil syndrome 1, autosomal dominant;Congenital anomaly of kidney and urinary tract (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDF6 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			2	95	1	98
missense	1		150	8	6	165
nonsense		1	1			2
start loss						0
frameshift		1				1
inframe indel			2	1		3
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding			41	12	26	79
Total	1	2	196	116	33

Variants in GDF6

This is a list of pathogenic ClinVar variants found in the GDF6 region.

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

Position	Type	Phenotype	Significance	ClinVar
8-96142347-G-A		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96142348-C-T		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96142349-G-A		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96142368-G-A		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96142374-A-G		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96142393-T-G		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96142441-G-A		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96142562-T-C		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)
8-96142585-C-T		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)
8-96142782-C-G		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96142892-G-A		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96143122-G-A		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96143132-CCT-C		Klippel-Feil syndrome	Likely benign (Jun 14, 2016)
8-96143425-C-T		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96143473-C-G		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)
8-96143479-G-T		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)
8-96143480-G-A		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96143508-C-T		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96143520-T-C		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96143565-C-G		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 12, 2018)
8-96143655-C-T		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96143672-C-T		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 12, 2018)
8-96143695-G-A		Klippel-Feil syndrome 1, autosomal dominant	Uncertain significance (Jan 13, 2018)
8-96143721-A-G		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)
8-96143782-C-T		Klippel-Feil syndrome 1, autosomal dominant	Benign (Jan 13, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDF6	protein_coding	protein_coding	ENST00000287020	2	18459

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.988	0.0117	125723	0	2	125725	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.934	204	245	0.832	0.0000118	2856
Missense in Polyphen		62	94.742	0.65441		1065
Synonymous	-0.394	119	114	1.05	0.00000593	989
Loss of Function	3.39	0	13.4	0.00	5.81e-7	149

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000932	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Growth factor that controls proliferation and cellular differentiation in the retina and bone formation. Plays a key role in regulating apoptosis during retinal development. Establishes dorsal-ventral positional information in the retina and controls the formation of the retinotectal map (PubMed:23307924). Required for normal formation of bones and joints in the limbs, skull, digits and axial skeleton. Plays a key role in establishing boundaries between skeletal elements during development. Regulation of GDF6 expression seems to be a mechanism for evolving species-specific changes in skeletal strucutres. Seems to positively regulates differentiation of chondrogenic tissue through the growth factor receptors subunits BMPR1A, BMPR1B, BMPR2 and ACVR2A, leading to the activation of SMAD1-SMAD5-SMAD8 complex. The regulation of chondrogenic differentiation is inhibited by NOG (PubMed:26643732). Also involved in the induction of adipogenesis from mesenchymal stem cells. This mechanism acts through the growth factor receptors subunits BMPR1A, BMPR2 and ACVR2A and the activation of SMAD1-SMAD5-SMAD8 complex and MAPK14/p38 (By similarity). {ECO:0000250|UniProtKB:P43028, ECO:0000269|PubMed:23307924, ECO:0000269|PubMed:26643732}.
• Disease: DISEASE: Klippel-Feil syndrome 1, autosomal dominant (KFS1) [MIM:118100]: A skeletal disorder characterized by congenital fusion of cervical vertebrae. It is due to a failure in the normal segmentation of vertebrae during the early weeks of fetal development. The clinical triad consists of short neck, low posterior hairline, and limited neck movement. Deafness is a feature in some cases and may be of sensorineural, conductive, or mixed type. {ECO:0000269|PubMed:18425797, ECO:0000269|PubMed:19129173}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving GDF6 has been found in a patient with Klippel-Feil syndrome (KFS). Paracentric inv(8)(q22;2q23.3). {ECO:0000269|PubMed:18425797}.; DISEASE: Microphthalmia, isolated, 4 (MCOP4) [MIM:613094]: 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. {ECO:0000269|PubMed:19129173, ECO:0000269|PubMed:24033328}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Leber congenital amaurosis 17 (LCA17) [MIM:615360]: A severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or almost absent pupillary responses, photophobia, high hyperopia and keratoconus. {ECO:0000269|PubMed:23307924}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Multiple synostoses syndrome 4 (SYNS4) [MIM:617898]: A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. SYNS4 inheritance is autosomal dominant. {ECO:0000269|PubMed:26643732, ECO:0000269|PubMed:29130651}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: TGF-beta signaling pathway - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);TGF-Core;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;TGF-beta super family signaling pathway canonical;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;GPCR signaling-G alpha i;BMP2 signaling TGF-beta MV;BMP signaling Dro (Consensus)

Recessive Scores

• pRec: 0.214

Haploinsufficiency Scores

• pHI: 0.536
• hipred: Y
• hipred_score: 0.806
• ghis: 0.488

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.984

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdf6
• Phenotype: 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); 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); limbs/digits/tail phenotype; vision/eye phenotype; skeleton phenotype; growth/size/body region phenotype; craniofacial phenotype

Zebrafish Information Network

• Gene name: gdf6a
• Affected structure: Muller cell
• Phenotype tag: abnormal
• Phenotype quality: disorganized

Gene ontology

• Biological process: apoptotic process;regulation of signaling receptor activity;positive regulation of pathway-restricted SMAD protein phosphorylation;BMP signaling pathway;positive regulation of chondrocyte differentiation;activin receptor signaling pathway;regulation of apoptotic process;regulation of MAPK cascade;fat cell differentiation;positive regulation of neuron differentiation;positive regulation of transcription, DNA-templated;cell development;pathway-restricted SMAD protein phosphorylation;SMAD protein signal transduction;positive regulation of p38MAPK cascade;retinal cell apoptotic process
• Cellular component: extracellular space
• Molecular function: cytokine activity;transforming growth factor beta receptor binding;growth factor activity;protein homodimerization activity