NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter) AND Charcot-Marie-Tooth disease type 4A

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000204463.14

Allele description [Variation Report for NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)]

NM_018972.4(GDAP1):c.487C>T (p.Gln163Ter)

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.487C>T (p.Gln163Ter)

HGVS:

NC_000008.11:g.74361886C>T
NG_008787.3:g.45757C>T
NM_001040875.4:c.283C>T
NM_001362929.2:c.160C>T
NM_001362930.2:c.313C>T
NM_001362931.2:c.487C>T
NM_001362932.2:c.160C>T
NM_018972.4:c.487C>TMANE SELECT
NP_001035808.1:p.Gln95Ter
NP_001349858.1:p.Gln54Ter
NP_001349859.1:p.Gln105Ter
NP_001349860.1:p.Gln163Ter
NP_001349861.1:p.Gln54Ter
NP_061845.2:p.Gln163Ter
LRG_244t1:c.487C>T
LRG_244:g.45757C>T
NC_000008.10:g.75274121C>T
NM_001040875.2:c.283C>T
NM_018972.2:c.487C>T

Protein change:

Q105*; GLN163TER

Links:

OMIM: 606598.0004; dbSNP: rs104894077

NCBI 1000 Genomes Browser:

rs104894077

Molecular consequence:

NM_001040875.4:c.283C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362929.2:c.160C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362930.2:c.313C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362931.2:c.487C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001362932.2:c.160C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018972.4:c.487C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Charcot-Marie-Tooth disease type 4A
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

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chondrolectin isoform 1 precursor [Mus musculus]
chondrolectin isoform 1 precursor [Mus musculus]
gi|110625876|ref|NP_624360.2|

Protein
Citrobacter freundii strain 874_CKOS 585_2955_371593, whole genome shotgun seque...
Citrobacter freundii strain 874_CKOS 585_2955_371593, whole genome shotgun sequence
gi|875300108|gb|JUPT01000200.1||gnl JUPT01|585_2955_371593

Nucleotide
Citrobacter freundii strain 873_CKOS 42_1336_206132, whole genome shotgun sequen...
Citrobacter freundii strain 873_CKOS 42_1336_206132, whole genome shotgun sequence
gi|875300219|gb|JUPU01000013.1||gnl JUPU01|42_1336_206132

Nucleotide
AGENCOURT_11031166 NICHD_XGC_OO1 Xenopus laevis cDNA clone IMAGE:6859363 5', mRN...
AGENCOURT_11031166 NICHD_XGC_OO1 Xenopus laevis cDNA clone IMAGE:6859363 5', mRNA sequence
gi|26031624|gnl|dbEST|15598947|gb|C 07.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000260870	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 17, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11743580, 12601710, 20849849, 28492532
SCV002058858	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:11743580,
SCV004174591	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000260870

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 17, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002058858

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 3, 2022)

germline

clinical testing

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

PMID:11743580,

SCV004174591

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]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	literature only, clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

CMT4A: identification of a Hispanic GDAP1 founder mutation.

Boerkoel CF, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, Mancias P, Papasozomenos SC, Stern LZ, Lupski JR.

Ann Neurol. 2003 Mar;53(3):400-5.

PubMed [citation]

PMID:: 12601710

Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations.

Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F, Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V.

Exp Neurol. 2011 Jan;227(1):31-41. doi: 10.1016/j.expneurol.2010.09.006. Epub 2010 Sep 21. Review.

PubMed [citation]

PMID:: 20849849

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000260870.11

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change creates a premature translational stop signal (p.Gln163*) in the GDAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GDAP1 are known to be pathogenic (PMID: 11743580). This variant is present in population databases (rs104894077, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Charcot-Marie-Tooth disease (PMID: 11743580, 12601710, 20849849). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4193). For these reasons, this variant has been classified as Pathogenic.

#	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

From 3billion, SCV002058858.1

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

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000076, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000004193, PMID:11743580, 3billion dataset). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Inherited Neuropathy Consortium Ii, University Of Miami, SCV004174591.1

#	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

Last Updated: Sep 29, 2024

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