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

Clinical significance:Pathogenic (Last evaluated: Aug 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000696667.3

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, type 4A (CMT4A)
Synonyms:
Charcot-Marie-Tooth disease, demyelinating, autosomal recessive; Charcot-Marie-Tooth disease, demyelinating, autosomal recessive, type 4a; Charcot-Marie-Tooth Neuropathy Type 4A
Identifiers:
MONDO: MONDO:0008961; MedGen: C1859198; Orphanet: 99948; OMIM: 214400

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000825239Invitaecriteria provided, single submitter
Pathogenic
(Aug 17, 2020)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

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

GDAP1 mutations in Italian axonal Charcot-Marie-Tooth patients: Phenotypic features and clinical course.

Pezzini I, Geroldi A, Capponi S, Gulli R, Schenone A, Grandis M, Doria-Lamba L, La Piana C, Cremonte M, Pisciotta C, Nolano M, Manganelli F, Santoro L, Mandich P, Bellone E.

Neuromuscul Disord. 2016 Jan;26(1):26-32. doi: 10.1016/j.nmd.2015.09.008. Epub 2015 Sep 16.

PubMed [citation]
PMID:
26525999
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000825239.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces histidine with arginine at codon 123 of the GDAP1 protein (p.His123Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to be de novo in individuals affected with Charcot-Marie-Tooth disease (PMID: 21753178). This variant has been observed to segregate with autosomal dominant Charcot-Marie-Tooth disease with reduced penetrance in several families, and is considered a founder mutation in the Finnish population (PMID: 21753178, 26525999, 23456260, 23963299). ClinVar contains an entry for this variant (Variation ID: 50558). Experimental studies have shown that this missense change causes an increase in mitochondrial store operated calcium entry in-vitro, suggesting a gain of protein function (PMID: 28220846). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2021

Support Center