NM_000166.6(GJB1):c.596G>A (p.Gly199Asp) AND Charcot-Marie-Tooth disease X-linked dominant 1

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Mar 22, 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:: RCV002052281.1

Allele description [Variation Report for NM_000166.6(GJB1):c.596G>A (p.Gly199Asp)]

NM_000166.6(GJB1):c.596G>A (p.Gly199Asp)

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.596G>A (p.Gly199Asp)

HGVS:

NC_000023.11:g.71224303G>A
NG_008357.1:g.14092G>A
NM_000166.6:c.596G>AMANE SELECT
NM_001097642.3:c.596G>A
NP_000157.1:p.Gly199Asp
NP_001091111.1:p.Gly199Asp
LRG_245t2:c.596G>A
LRG_245:g.14092G>A
LRG_245p2:p.Gly199Asp
NC_000023.10:g.70444153G>A

Protein change:

G199D

Links:

dbSNP: rs2147946811

NCBI 1000 Genomes Browser:

rs2147946811

Molecular consequence:

NM_000166.6:c.596G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001097642.3:c.596G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Charcot-Marie-Tooth disease X-linked dominant 1
Synonyms:: CHARCOT-MARIE-TOOTH NEUROPATHY, X-LINKED, 1; CMTX 1; Charcot-Marie-Tooth peroneal muscular atrophy, X-linked; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0010549; MedGen: C0393808; Orphanet: 101075; OMIM: 302800

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serpin B6 isoform a [Homo sapiens]
serpin B6 isoform a [Homo sapiens]
gi|41152086|ref|NP_004559.4|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002318914	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 22, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 9099841, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002318914

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 22, 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	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1).

Janssen EA, Kemp S, Hensels GW, Sie OG, de Die-Smulders CE, Hoogendijk JE, de Visser M, Bolhuis PA.

Hum Genet. 1997 Apr;99(4):501-5.

PubMed [citation]

PMID:: 9099841

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From 3billion, SCV002318914.1

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

Description

Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:9099841). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.789>=0.6, 3CNET: 0.928>=0.75). A missense variant is a common mechanism. It is not observed in the gnomAD v2.1.1 dataset. Therefore, this variant is classified as uncertain significance 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

Last Updated: Dec 24, 2023

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