NM_000166.6(GJB1):c.299A>T (p.His100Leu) AND Charcot-Marie-Tooth Neuropathy X

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 6, 2020
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:: RCV001303696.7

Allele description [Variation Report for NM_000166.6(GJB1):c.299A>T (p.His100Leu)]

NM_000166.6(GJB1):c.299A>T (p.His100Leu)

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.299A>T (p.His100Leu)

HGVS:

NC_000023.11:g.71224006A>T
NG_008357.1:g.13795A>T
NM_000166.6:c.299A>TMANE SELECT
NM_001097642.3:c.299A>T
NP_000157.1:p.His100Leu
NP_001091111.1:p.His100Leu
LRG_245t2:c.299A>T
LRG_245:g.13795A>T
LRG_245p2:p.His100Leu
NC_000023.10:g.70443856A>T
NM_000166.5:c.299A>T

Protein change:

H100L

Links:

dbSNP: rs1602349133

NCBI 1000 Genomes Browser:

rs1602349133

Molecular consequence:

NM_000166.6:c.299A>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.299A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001492949	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 6, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20730878, 9452099, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001492949

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 6, 2020)

germline

clinical testing

PubMed (3)
[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

Mutation in connexin 32 causes Charcot-Marie-Tooth disease in a large Chinese family.

Guo F, Shi Y, Lin Y, Liu X, Liu B, Liu Y, Yang Y, Lu F, Ma S, Yang Z.

Muscle Nerve. 2010 Nov;42(5):715-21. doi: 10.1002/mus.21756.

PubMed [citation]

PMID:: 20730878

Mutation analysis in Charcot-Marie-Tooth disease type 1 (CMT1).

Sorour E, Upadhyaya M.

Hum Mutat. 1998;Suppl 1:S242-7. No abstract available.

PubMed [citation]

PMID:: 9452099

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001492949.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant has not been reported in the literature in individuals with GJB1-related conditions. 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.His100 amino acid residue in GJB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20730878, 9452099). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with leucine at codon 100 of the GJB1 protein (p.His100Leu). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and leucine.

#	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: May 7, 2024

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