NM_004004.6(GJB2):c.445G>A (p.Ala149Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 15, 2022
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:: RCV000037854.5

Allele description [Variation Report for NM_004004.6(GJB2):c.445G>A (p.Ala149Thr)]

NM_004004.6(GJB2):c.445G>A (p.Ala149Thr)

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.445G>A (p.Ala149Thr)

HGVS:

NC_000013.11:g.20189137C>T
NG_008358.1:g.8839G>A
NM_004004.6:c.445G>AMANE SELECT
NP_003995.2:p.Ala149Thr
LRG_1350t1:c.445G>A
LRG_1350:g.8839G>A
LRG_1350p1:p.Ala149Thr
NC_000013.10:g.20763276C>T
NM_004004.5:c.445G>A
c.445G>A

Protein change:

A149T

Links:

dbSNP: rs111033225

NCBI 1000 Genomes Browser:

rs111033225

Molecular consequence:

NM_004004.6:c.445G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

Recent activity

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Homo sapiens transmembrane protein 127 (TMEM127), transcript variant 1, mRNA
Homo sapiens transmembrane protein 127 (TMEM127), transcript variant 1, mRNA
gi|305682550|ref|NM_017849.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061516	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (May 22, 2013)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10982180, 15146474, 23073770, 24033266
SCV002766245	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 15, 2022)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10982180, 15146474, 22567861, 16300957, 30245029, 33297549, 23073770, 11445873, 25012701 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061516

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(May 22, 2013)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002766245

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 15, 2022)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Molecular basis of childhood deafness resulting from mutations in the GJB2 (connexin 26) gene.

Rabionet R, Zelante L, López-Bigas N, D'Agruma L, Melchionda S, Restagno G, Arbonés ML, Gasparini P, Estivill X.

Hum Genet. 2000 Jan;106(1):40-4.

PubMed [citation]

PMID:: 10982180

See all PubMed Citations (10)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061516.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (4)

Description

The Ala149Thr variant in GJB2 has been identified in 6 probands with hearing los s and in 1/584 control chromosomes (Toth 2004, Rabionet 2000, Hashemi 2012, Bliz netz 2012, LMM unpublished data). Only one of these probands carried a second pa thogenic variant on the other allele of GJB2 (Toth 2003). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIF T) suggest that the variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, additional infor mation is needed to fully assess the variant's clinical significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	2	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002766245.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

Variant summary: GJB2 c.445G>A (p.Ala149Thr) results in a non-conservative amino acid change located in the Connexin, N-terminal domain (IPR013092) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251006 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (5.6e-05 vs 0.00034), allowing no conclusion about variant significance. c.445G>A has been reported in the literature as a non-informative genotype (second allele not specified) or as a presumed compound heterozygous genotype in individuals reportedly affected with congenital/AR-Non-Syndromic Hearing Loss/Familial Hearing Impairment (example, Rabionet_2000, Toth_2001, Toth_2004, Hashemi_2012, Bliznets_2012, Garcia-Garcia_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

#	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: Mar 10, 2024

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