NM_018972.4(GDAP1):c.776A>G (p.Lys259Arg) AND Charcot-Marie-Tooth disease type 4A

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 8, 2021
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:: RCV000556352.8

Allele description [Variation Report for NM_018972.4(GDAP1):c.776A>G (p.Lys259Arg)]

NM_018972.4(GDAP1):c.776A>G (p.Lys259Arg)

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.776A>G (p.Lys259Arg)

HGVS:

NC_000008.11:g.74364066A>G
NG_008787.3:g.47937A>G
NM_001040875.4:c.572A>G
NM_001362929.2:c.449A>G
NM_001362930.2:c.602A>G
NM_001362931.2:c.694+1013A>G
NM_001362932.2:c.449A>G
NM_018972.4:c.776A>GMANE SELECT
NP_001035808.1:p.Lys191Arg
NP_001349858.1:p.Lys150Arg
NP_001349859.1:p.Lys201Arg
NP_001349861.1:p.Lys150Arg
NP_061845.2:p.Lys259Arg
LRG_244t1:c.776A>G
LRG_244:g.47937A>G
NC_000008.10:g.75276301A>G
NM_018972.2:c.776A>G

Protein change:

K150R

Links:

dbSNP: rs778557691

NCBI 1000 Genomes Browser:

rs778557691

Molecular consequence:

NM_001362931.2:c.694+1013A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_001040875.4:c.572A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362929.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362930.2:c.602A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001362932.2:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_018972.4:c.776A>G - missense variant - [Sequence Ontology: SO:0001583]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000644080	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 8, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000644080

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 8, 2021)

germline

clinical testing

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000644080.5

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

Description

This variant has not been reported in the literature in individuals with GDAP1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with arginine at codon 259 of the GDAP1 protein (p.Lys259Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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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