NM_000166.6(GJB1):c.635T>G (p.Leu212Arg) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 14, 2022
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:: RCV001039171.9

Allele description [Variation Report for NM_000166.6(GJB1):c.635T>G (p.Leu212Arg)]

NM_000166.6(GJB1):c.635T>G (p.Leu212Arg)

Gene:

GJB1:gap junction protein beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

Xq13.1

Genomic location:

Preferred name:

NM_000166.6(GJB1):c.635T>G (p.Leu212Arg)

HGVS:

NC_000023.11:g.71224342T>G
NG_008357.1:g.14131T>G
NM_000166.6:c.635T>GMANE SELECT
NM_001097642.3:c.635T>G
NP_000157.1:p.Leu212Arg
NP_001091111.1:p.Leu212Arg
LRG_245t2:c.635T>G
LRG_245:g.14131T>G
LRG_245p2:p.Leu212Arg
NC_000023.10:g.70444192T>G
NM_000166.5:c.635T>G

Protein change:

L212R

Links:

dbSNP: rs2092546062

NCBI 1000 Genomes Browser:

rs2092546062

Molecular consequence:

NM_000166.6:c.635T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.635T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Charcot-Marie-Tooth Neuropathy X
Identifiers:: MedGen: CN118851

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LOW QUALITY PROTEIN: olfactory receptor 2M3-like [Mus caroli]
LOW QUALITY PROTEIN: olfactory receptor 2M3-like [Mus caroli]
gi|1195692852|ref|XP_021040178.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001202685	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20039784, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001202685

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 14, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Six new gap junction beta 1 gene mutations and their phenotypic expression in Czech patients with Charcot-Marie-Tooth disease.

Brozková D, Mazanec R, Haberlová J, Sakmaryová I, Subrt I, Seeman P.

Genet Test Mol Biomarkers. 2010 Feb;14(1):3-7. doi: 10.1089/gtmb.2009.0093.

PubMed [citation]

PMID:: 20039784

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, SCV001202685.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. This variant disrupts the p.Leu212 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20039784). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 837766). This missense change has been observed in individual(s) with motor and sensory neuropathy (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the GJB1 protein (p.Leu212Arg).

#	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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