NM_018972.4(GDAP1):c.368A>G (p.His123Arg) AND Charcot-Marie-Tooth disease axonal type 2K

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 25, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000043549.9

Allele description [Variation Report for NM_018972.4(GDAP1):c.368A>G (p.His123Arg)]

NM_018972.4(GDAP1):c.368A>G (p.His123Arg)

Gene:

GDAP1:ganglioside induced differentiation associated protein 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q21.11

Genomic location:

Preferred name:

NM_018972.4(GDAP1):c.368A>G (p.His123Arg)

HGVS:

NC_000008.11:g.74360194A>G
NG_008787.3:g.44065A>G
NM_001040875.4:c.164A>G
NM_001362929.2:c.41A>G
NM_001362930.2:c.311-1690A>G
NM_001362931.2:c.368A>G
NM_001362932.2:c.41A>G
NM_018972.4:c.368A>GMANE SELECT
NP_001035808.1:p.His55Arg
NP_001349858.1:p.His14Arg
NP_001349860.1:p.His123Arg
NP_001349861.1:p.His14Arg
NP_061845.2:p.His123Arg
LRG_244t1:c.368A>G
LRG_244:g.44065A>G
NC_000008.10:g.75272429A>G
NM_001040875.2:c.164A>G
NM_018972.2:c.368A>G

Protein change:

H123R; HIS123ARG

Links:

OMIM: 606598.0018; dbSNP: rs397515442

NCBI 1000 Genomes Browser:

rs397515442

Molecular consequence:

NM_001362930.2:c.311-1690A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001040875.4:c.164A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362929.2:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362931.2:c.368A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362932.2:c.41A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_018972.4:c.368A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth disease axonal type 2K
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, AXONAL, TYPE 2K; Charcot-Marie-Tooth disease type 2K; Charcot-Marie-Tooth disease, axonal, autosomal recessive, Type 2K
Identifiers:: MONDO: MONDO:0011916; MedGen: C1842983; Orphanet: 99944; OMIM: 607831

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000071290	OMIM	no assertion criteria provided	Pathogenic (Aug 9, 2011)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004174616	Inherited Neuropathy Consortium Ii, University Of Miami	no assertion criteria provided	Uncertain significance (Jan 6, 2016)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV004805592	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 25, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000071290

OMIM

no assertion criteria provided

Pathogenic
(Aug 9, 2011)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004174616

Inherited Neuropathy Consortium Ii, University Of Miami

no assertion criteria provided

Uncertain significance
(Jan 6, 2016)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV004805592

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 25, 2024)

germline

research

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Dominant GDAP1 mutations cause predominantly mild CMT phenotypes.

Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J, Schindler AB, Cornblath DR, Fischbeck KH, Auer-Grumbach M, Guelly C, Huber N, De Vriendt E, Timmerman V, Suter U, Hausmanowa-Petrusewicz I, Niemann A, Kochański A, De Jonghe P, Jordanova A.

Neurology. 2011 Aug 9;77(6):540-8. doi: 10.1212/WNL.0b013e318228fc70. Epub 2011 Jul 13.

PubMed [citation]

PMID:: 21753178
PMCID:: PMC3272385

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From OMIM, SCV000071290.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In 3 affected members of a large Finnish family with autosomal dominant Charcot-Marie-Tooth disease type 2K (CMT2K; see 607831), Zimon et al. (2011) identified a heterozygous c.358A-G transition in the GDAP1 gene, resulting in a his123-to-arg (H123R) substitution. (The nucleotide numbering was based on a revised transcript.) Four older asymptomatic family members also carried the mutation, indicating incomplete penetrance. The mutation was not found in 280 control individuals. The phenotype was variable, with onset of difficulty walking due to distal muscle weakness and atrophy between 3 and 32 years of age. The disorder was slowly progressive, and all patients remained ambulatory. One patient had proximal weakness. Nerve conduction studies showed an axonal pattern. A heterozygous H123R mutation occurred de novo in a patient of Tunisian origin who was more severely affected and showed delayed motor development; that patient had intermediate results on electrophysiologic studies.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Inherited Neuropathy Consortium Ii, University Of Miami, SCV004174616.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805592.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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