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

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 20, 2023
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:: RCV000037862.7

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

NCBI 1000 Genomes Browser:

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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nicotinamide riboside kinase 1 isoform X1 [Homo sapiens]
nicotinamide riboside kinase 1 isoform X1 [Homo sapiens]
gi|767957777|ref|XP_011517119.1|

Protein
Homo sapiens cyclin G associated kinase (GAK), transcript variant 1, mRNA
Homo sapiens cyclin G associated kinase (GAK), transcript variant 1, mRNA
gi|970414585|ref|NM_005255.3|

Nucleotide

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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 (Apr 20, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 12172394, 26346709, 25555641, 33914963 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
(Apr 20, 2023)

germline

clinical testing

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

Citation Link

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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

Assessment of denaturing high-performance liquid chromatography (DHPLC) in screening for mutations in connexin 26 (GJB2).

Lin D, Goldstein JA, Mhatre AN, Lustig LR, Pfister M, Lalwani AK.

Hum Mutat. 2001;18(1):42-51.

PubMed [citation]

PMID:: 11438992

Mutation analysis of familial GJB2-related deafness in Iranian Azeri Turkish patients.

Bonyadi M, Esmaeili M, Abhari M, Lotfi A.

Genet Test Mol Biomarkers. 2009 Oct;13(5):689-92. doi: 10.1089/gtmb.2009.0026.

PubMed [citation]

PMID:: 19715472

See all PubMed Citations (14)

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, SCV003929343.1

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

Description

Variant summary: GJB2 c.511G>A (p.Ala171Thr) results in a non-conservative amino acid change located in the Gap junction protein, cysteine-rich domain (IPR019570) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251052 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GJB2 causing Non-Syndromic Hearing Loss (0.00013 vs 0.00034), allowing no conclusion about variant significance. c.511G>A has been reported in the literature in individuals affected with Non-Syndromic Hearing Loss (e.g. Wu_2002, Kashef_2015, Carranza_2016) and palmoplantar keratoderma (Harjama_2021). 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. Six ClinVar submitters have assessed the variant since 2014: one classified the variant as benign, and five as uncertain significance. 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: Sep 29, 2024

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