NM_004004.6(GJB2):c.493C>T (p.Arg165Trp) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jan 29, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000724444.19

Allele description [Variation Report for NM_004004.6(GJB2):c.493C>T (p.Arg165Trp)]

NM_004004.6(GJB2):c.493C>T (p.Arg165Trp)

Gene:

GJB2:gap junction protein beta 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q12.11

Genomic location:

Preferred name:

NM_004004.6(GJB2):c.493C>T (p.Arg165Trp)

HGVS:

NC_000013.11:g.20189089G>A
NG_008358.1:g.8887C>T
NM_004004.6:c.493C>TMANE SELECT
NP_003995.2:p.Arg165Trp
LRG_1350t1:c.493C>T
LRG_1350:g.8887C>T
LRG_1350p1:p.Arg165Trp
NC_000013.10:g.20763228G>A
NM_004004.5:c.493C>T
P29033:p.Arg165Trp

Protein change:

R165W

Links:

UniProtKB: P29033#VAR_015942; dbSNP: rs376898963

NCBI 1000 Genomes Browser:

rs376898963

Molecular consequence:

NM_004004.6:c.493C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000227304	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Nov 19, 2014)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001083004	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely benign (Jan 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001143672	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Uncertain significance (May 17, 2019)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 11494963, 29921236, 20863150, 15617550, 12746422, 20086306, 20234132, 29148562, 25447126, 18607988, 18941476, 26467025
SCV001801649	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Mar 5, 2021)	germline	clinical testing	Citation Link

Help

Summary from all submissions

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

Recurrent mutations in the deafness gene GJB2 (connexin 26) in British Asian families.

Rickard S, Kelsell DP, Sirimana T, Rajput K, MacArdle B, Bitner-Glindzicz M.

J Med Genet. 2001 Aug;38(8):530-3. No abstract available.

PubMed [citation]

PMID:: 11494963
PMCID:: PMC1734923

See all PubMed Citations (13)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000227304.5

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

#	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		1	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001083004.6

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

#	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 Athena Diagnostics, SCV001143672.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

#	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 GeneDx, SCV001801649.1

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

Description

Observed as heterozygous variant without a second pathogenic variant in multiple individuals with hearing loss but also in unaffected relatives in published literature (Rickard et al., 2001; Putcha et al., 2007; Vanniya et al., 2017; Gurtler et al., 2008; Amritkumar et al., 2018); Located in the second extracellular domain of Cx26; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32425985, 31992338, 30245029, 20863150, 29542069, 29148562, 16950989, 12746422, 20234132, 17666888, 18607988, 20086306, 18941476, 29921236, 25388846, 11494963, 15617550)

#	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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