GDAP1

ganglioside induced differentiation associated protein 1

Basic information

Region (hg38): 8:74320613-74518007

Previous symbols: [ "CMT4A" ]

Links

ENSG00000104381 ∙ NCBI:54332 ∙ OMIM:606598 ∙ HGNC:15968 ∙ Uniprot:Q8TB36 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant Charcot-Marie-Tooth disease type 2K (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 4A (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2K (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease recessive intermediate A (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease recessive intermediate A (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2K (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, recessive intermediate, A; Charcot-Marie-Tooth disease, axonal, with vocal cord paresis; Charcot-Marie-Tooth disease, axonal, type 2K; Charcot-Marie-Tooth disease, type 4A	AD/AR	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	Neurologic	11743579; 11743580; 12499475; 12707075; 12566285; 15805163; 17039978; 18492089; 20685671; 21753178; 22200116; 22971097

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GDAP1 gene.

• Charcot-Marie-Tooth_disease_type_4A (376 variants)
• not_provided (121 variants)
• Charcot-Marie-Tooth_disease (86 variants)
• Charcot-Marie-Tooth_disease_axonal_type_2K (85 variants)
• Inborn_genetic_diseases (65 variants)
• Charcot-Marie-Tooth_disease_recessive_intermediate_A (47 variants)
• Charcot-Marie-Tooth_disease,_axonal,_with_vocal_cord_paresis,_autosomal_recessive (40 variants)
• not_specified (25 variants)
• GDAP1-related_disorder (5 variants)
• Autosomal_dominant_Charcot-Marie-Tooth_disease_type_2K (5 variants)
• Peripheral_neuropathy (3 variants)
• Tip-toe_gait (2 variants)
• Neuropathy,_axonal,_with_vocal_cord_paresis,_autosomal_recessive (2 variants)
• Charcot-Marie-Tooth_disease,_type_I (2 variants)
• Charcot-Marie-Tooth_disease_type_4 (1 variants)
• Peripheral_axonal_neuropathy (1 variants)
• Charcot-Marie-Tooth_with_Vocal_Cord_Paresis (1 variants)
• Polyneuropathy (1 variants)
• Elevated_circulating_creatine_kinase_concentration (1 variants)
• Sensory_neuropathy (1 variants)
• Charcot-Marie-Tooth,_Intermediate (1 variants)
• Pes_cavus (1 variants)
• Elevated_circulating_alkaline_phosphatase_concentration (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GDAP1 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000018972.4. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	83	1	86
missense	9	44	209	2		264
nonsense	13	10	2			25
start loss	1	2				3
frameshift	25	13	6			44
splice donor/acceptor (+/-2bp)	2	6	2			10
Total	50	75	221	85	1

Highest pathogenic variant AF is 0.0003453758

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GDAP1	protein_coding	protein_coding	ENST00000220822	6	167743

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.24e-8	0.539	125696	0	52	125748	0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.00	150	189	0.795	0.0000104	2339
Missense in Polyphen		67	87.536	0.7654		1046
Synonymous	-0.510	77	71.5	1.08	0.00000398	682
Loss of Function	1.03	14	18.8	0.743	0.00000115	217

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000759	0.000759
Ashkenazi Jewish	0.00	0.00
East Asian	0.000217	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.000150	0.000149
Middle Eastern	0.000217	0.000217
South Asian	0.000196	0.000196
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Regulates the mitochondrial network by promoting mitochondrial fission. {ECO:0000269|PubMed:16172208}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 4A (CMT4A) [MIM:214400]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. CMT4A is a severe form characterized by early age of onset and rapid progression leading to inability to walk in late childhood or adolescence. {ECO:0000269|PubMed:11743579, ECO:0000269|PubMed:12601710, ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive (CMT2RV) [MIM:607706]: A form of Charcot-Marie-Tooth disease characterized by the association of axonal neuropathy with vocal cord paresis. Charcot-Marie-Tooth disease is a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. {ECO:0000269|PubMed:12868504, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2K (CMT2K) [MIM:607831]: An axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. Charcot-Marie-Tooth disease type 2K onset is in early childhood (younger than 3 years). This phenotype is characterized by foot deformities, kyphoscoliosis, distal limb muscle weakness and atrophy, areflexia, and diminished sensation in the lower limbs. Weakness in the upper limbs is observed in the first decade, with clawing of the fingers. Inheritance can be autosomal dominant or recessive. {ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:20685671, ECO:0000269|PubMed:22206013, ECO:0000269|PubMed:26525999, ECO:0000269|PubMed:28244113}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease, recessive, intermediate type, A (CMTRIA) [MIM:608340]: A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec. {ECO:0000269|PubMed:12499475, ECO:0000269|PubMed:12566285, ECO:0000269|PubMed:15772096, ECO:0000269|PubMed:16172208}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.163

Intolerance Scores

• loftool: 0.213
• rvis_EVS: -0.69
• rvis_percentile_EVS: 14.97

Haploinsufficiency Scores

• pHI: 0.174
• hipred: N
• hipred_score: 0.462
• ghis: 0.652

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.808

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Gdap1
• 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; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: gdap1
• Affected structure: peripheral neuron
• Phenotype tag: abnormal
• Phenotype quality: branchiness

Gene ontology

• Biological process: mitochondrial fission;protein targeting to mitochondrion;mitochondrion organization;mitochondrial fusion;response to retinoic acid;cellular response to vitamin D
• Cellular component: nucleus;mitochondrion;cytosol;membrane;integral component of mitochondrial outer membrane