NM_004004.6(GJB2):c.511G>A (p.Ala171Thr) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 30, 2025
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:: RCV000037862.8

Allele description [Variation Report for NM_004004.6(GJB2):c.511G>A (p.Ala171Thr)]

NM_004004.6(GJB2):c.511G>A (p.Ala171Thr)

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.511G>A (p.Ala171Thr)

HGVS:

NC_000013.11:g.20189071C>T
NG_008358.1:g.8905G>A
NM_004004.6:c.511G>AMANE SELECT
NP_003995.2:p.Ala171Thr
LRG_1350t1:c.511G>A
LRG_1350:g.8905G>A
LRG_1350p1:p.Ala171Thr
NC_000013.10:g.20763210C>T
NM_004004.5:c.511G>A
c.511G>A

Protein change:

A171T

Links:

dbSNP: rs201004645

Molecular consequence:

NM_004004.6:c.511G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000061524	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Jun 23, 2016)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11438992, 19715472, 19043807, 15603707, 11968091, 15365987, 17357124, 12172394, 17666888, 24529908, 24033266
SCV003929343	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Dec 30, 2025)	germline	clinical testing	PubMed (42) [See all records that cite these PMIDs] 15365987, 11968091, 12172394, 12172392, 17666888, 21868108, 21287563, 22991996, 22695344, 19043807, 17357124, 19715472, 24529908, 25087612, 25388846, 25788563, 26346709, 27153395, 30245029, 31569309, 31620696, 32090102, 25555641, 28483220, 18368581, 33914963, 36048236, 21777984, 34652575, 25587757, 25447126, 34581455, 20739942, 28102197, 29501291, 31523594, 31834214, 21510145, 40493033, 22172221, 11438992, 15603707 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000061524

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Uncertain significance
(Jun 23, 2016)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV003929343

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Dec 30, 2025)

germline

clinical testing

PubMed (42)
[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

GJB2: the spectrum of deafness-causing allele variants and their phenotype.

Azaiez H, Chamberlin GP, Fischer SM, Welp CL, Prasad SD, Taggart RT, del Castillo I, Van Camp G, Smith RJ.

Hum Mutat. 2004 Oct;24(4):305-11.

PubMed [citation]

PMID:: 15365987
PMCID:: PMC10519371

See all PubMed Citations (43)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000061524.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (11)

Description

Variant classified as Uncertain Significance - Favor Benign. The p.Ala171Thr var iant in GJB2 has been previously reported in nine individuals with sensorineural hearing loss (Lin 2001, Najmabadi 2002, Wu 2002, Xiao 2004, Azaiez 2004, Putcha 2007, Samanich 2007, Han 2008, Bonyadi 2009, Bonyadi 2014, LMM data). However, a variant affecting the remaining copy of GJB2 was not identified in any of them . In addition, two individuals had cochlear malformations inconsistent with GJB 2-related hearing loss (Lin 2001, Wu 2002). One publication suggested that p.Ala 171Thr could be inherited in a dominant pattern (Xiao 2004); however, this is in consistent with findings from other studies. This variant has been identified i n two individuals with normal hearing (Samanich 2007, Han 2008) and has been ide ntified in 8/66556 European chromosomes by the Exome Aggregation Consortium (ExA C, http://exac.broadinstitute.org; dbSNP rs201004645). Computational prediction tools and conservation analysis suggest that the p.Ala171Thr variant may not imp act the protein, though this information is not predictive enough to rule out pa thogenicity. In summary, while the clinical significance of the p.Ala171Thr vari ant is uncertain, these data suggest that it is more likely to be benign.

#	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, SCV003929343.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (42)

Description

Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes. This frequency is not significantly higher than estimated for disease-causing variants in GJB2 (autosomal recessive nonsyndromic deafness), allowing no conclusion about variant significance. However, the frequency does exceed the maximum pathogenic allele frequency estimated for autosomal dominant nonsyndromic deafness, suggesting that this variant is unlikely to be causative for that phenotype. c.511G>A has been observed in the heterozygous state in numerous individual(s) affected with autosomal dominant or autosomal recessive Non-Syndromic Hearing Loss, without strong evidence for causality and/or unclear inheritance (example, Wu_2002, Kashef_2015, Davarnia_2012, Bonyadi_2014, Najmabadi_2002, Putcha_2007, Lipan_2011, Nishio_2015, Bazazzadegan_2012, Azaiez_2004, Lin_2001, Chen_2011, Bonyadi_2009, Xiao_2004) but was also observed in the compound heterozygous state in at least 1 individual with autosomal recessive nonsyndromic deafness (Carranza_2016, Carranza_2017). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 26346709, 33914963, 25555641, 12172394, 22172221, 24529908, 11968091, 17666888, 15603707, 21287563, 25788563, 22695344, 15365987, 11438992, 21777984, 19715472, 26346709, 36048236, 34652575, 31523594, 30245029, 21868108, 18368581, 20739942, 31569309, 22991996, 31620696, 31834214, 21510145, 32090102, 40493033, 19043807, 28483220, 12172392, 25587757, 25388846, 29501291, 28102197, 27153395, 25447126, 25087612, 17357124, 34581455). ClinVar contains an entry for this variant (Variation ID: 44758). Based on the evidence outlined above, the variant was classified as 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

Last Updated: Apr 12, 2026

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