NM_004004.6(GJB2):c.487A>G (p.Met163Val) AND not provided

Germline classification:: Uncertain significance (5 submissions)
Last evaluated:: Mar 5, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001092709.30

Allele description [Variation Report for NM_004004.6(GJB2):c.487A>G (p.Met163Val)]

NM_004004.6(GJB2):c.487A>G (p.Met163Val)

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.487A>G (p.Met163Val)

HGVS:

NC_000013.11:g.20189095T>C
NG_008358.1:g.8881A>G
NM_004004.6:c.487A>GMANE SELECT
NP_003995.2:p.Met163Val
LRG_1350t1:c.487A>G
LRG_1350:g.8881A>G
LRG_1350p1:p.Met163Val
NC_000013.10:g.20763234T>C
NM_004004.5:c.487A>G
c.487A>G

Protein change:

M163V

Links:

dbSNP: rs80338949

NCBI 1000 Genomes Browser:

rs80338949

Molecular consequence:

NM_004004.6:c.487A>G - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

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cytochrome b (mitochondrion) [Thraupis sayaca]
cytochrome b (mitochondrion) [Thraupis sayaca]
gi|2317753558|gb|UYG47231.1|

Protein
Mus musculus lectin, galactose binding, soluble 9 (Lgals9), transcript variant 2...
Mus musculus lectin, galactose binding, soluble 9 (Lgals9), transcript variant 2, mRNA
gi|226531138|ref|NM_001159301.1|

Nucleotide
cytochrome b, partial (mitochondrion) [Megastigmus spermotrophus nigrodorsatus]
cytochrome b, partial (mitochondrion) [Megastigmus spermotrophus nigrodorsatus]
gi|60250701|gb|AAX14884.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061522	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 30, 2022)	germline	clinical testing	PubMed (17) [See all records that cite these PMIDs] 11493200, 17041943, 14643477, 15964725, 12872268, 12189487, 20086291, 19715472, 16380907, 19929407, 12505163, 22208444, 26096904, 19941053, 24529908, 21388256, 25741868
SCV001249345	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Jan 1, 2023)	germline	clinical testing	Citation Link,
SCV001784037	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Mar 5, 2024)	germline	clinical testing	Citation Link,
SCV003510273	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 26, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11493200, 12189487, 21281533, 22208444, 26096904, 12505163, 28428247, 28492532
SCV003816811	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	2	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DNA sequence analysis of GJB2, encoding connexin 26: observations from a population of hearing impaired cases and variable carrier rates, complex genotypes, and ethnic stratification of alleles among controls.

Tang HY, Fang P, Ward PA, Schmitt E, Darilek S, Manolidis S, Oghalai JS, Roa BB, Alford RL.

Am J Med Genet A. 2006 Nov 15;140(22):2401-15. Erratum in: Am J Med Genet A. 2008 Nov 15;146A(22):2979..

PubMed [citation]

PMID:: 17041943
PMCID:: PMC3623690

GJB2 gene mutations causing familial hereditary deafness in Turkey.

Bayazit YA, Cable BB, Cataloluk O, Kara C, Chamberlin P, Smith RJ, Kanlikama M, Ozer E, Cakmak EA, Mumbuc S, Arslan A.

Int J Pediatr Otorhinolaryngol. 2003 Dec;67(12):1331-5.

PubMed [citation]

PMID:: 14643477

See all PubMed Citations (20)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061522.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (17)

Description

The p.Met163Val variant in GJB2 has been identified in >10 probands with non-syndromic hearing loss from several ethnic populations; however, a pathogenic variant on the second allele of GJB2 was not detected in any of these probands (Al-Qahtani 2010, Amorini 2015, Bayazit 2003, Bonyadi 2009, Bonyadi 2014, Chaleshtori 2002, Chaleshtori 2005, Dalamon 2005, Falah 2012, Gunther 2003, Janecke 2002, Mahdieh 2011, Marlin 2001, Padma 2009, Tang 2006, Yilmaz 2010). In two families with post-lingual progressive hearing loss described in one study, two parent-to-child segregations were reported for this variant suggesting that the variant may lead to autosomal dominant hearing loss (Falah 2012). However, the majority of probands in the other studies did not report autosomal dominant inheritance of hearing loss. Two other missense variants at the same amino acid position (p.Met163Leu and p.Met163Thr) have also been reported in individuals with hearing loss, and in vitro functional studies of the p.Met163Val and p.Met163Leu show an impact to the normal activity of the protein due to these variants (Bruzzone 2003, Matos 2008). This data suggests that variants at this amino acid position are not tolerated. The p.Met163Val variant has also been identified 10/16478 South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80338949); however this frequency is not high enough to rule out pathogenicity. In summary, the presence of the p.Met163Val variant in several affected individuals and the functional data suggests a pathogenic role for the variant, however the clinical significance of this variant cannot be determined with certainty given the absence of a second pathogenic variant in heterozygous probands and limited segregation data. ACMG/AMP Criteria applied:BS1, PP3.

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001249345.26

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

Description

GJB2: PS4:Supporting

#	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		2	not provided	not provided	not provided

From GeneDx, SCV001784037.3

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

Description

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the heterozygous state with no other GJB2 variant in multiple individuals with hearing loss in published literature (PMID: 11493200, 19929407, 12189487, 20086306); Published functional studies demonstrate a damaging effect on gap junction function (PMID: 28428247, 12505163); Observed in unaffected parents of children with hearing loss who were heterozygous for the variant in published literature (PMID: 28263784, 19715472); This variant is associated with the following publications: (PMID: 25388846, 19941053, 12505163, 20086291, 24529908, 22208444, 24158611, 12189487, 21996152, 14643477, 21388256, 22695344, 19929407, 15964725, 30989077, 19715472, 20086306, 16380907, 17041943, 12872268, 31620696, 34426522, 34335733, Chaleshtori2005[article], 33096615, 31569309, 21281533, 31412945, 37892203, 37106706, 36833326, 38378725, 11493200, 28428247, 28263784, 26096904)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003510273.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 163 of the GJB2 protein (p.Met163Val). This variant is present in population databases (rs80338949, gnomAD 0.07%). This missense change has been observed in individual(s) with deafness (PMID: 11493200, 12189487, 21281533, 22208444, 26096904). ClinVar contains an entry for this variant (Variation ID: 21388). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GJB2 protein function. Experimental studies have shown that this missense change affects GJB2 function (PMID: 12505163, 28428247). 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

From Revvity Omics, Revvity, SCV003816811.2

#	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

Last Updated: Oct 20, 2024

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