NM_004004.6(GJB2):c.632G>A (p.Cys211Tyr) AND Nonsyndromic genetic hearing loss

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 4, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001251624.1

Allele description [Variation Report for NM_004004.6(GJB2):c.632G>A (p.Cys211Tyr)]

NM_004004.6(GJB2):c.632G>A (p.Cys211Tyr)

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.632G>A (p.Cys211Tyr)

HGVS:

NC_000013.11:g.20188950C>T
NG_008358.1:g.9026G>A
NM_004004.6:c.632G>AMANE SELECT
NP_003995.2:p.Cys211Tyr
LRG_1350t1:c.632G>A
LRG_1350:g.9026G>A
LRG_1350p1:p.Cys211Tyr
NC_000013.10:g.20763089C>T

Protein change:

C211Y

Links:

dbSNP: rs1268045311

NCBI 1000 Genomes Browser:

rs1268045311

Molecular consequence:

NM_004004.6:c.632G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Nonsyndromic genetic hearing loss
Synonyms:: Nonsyndromic hearing loss and deafness; Non-syndromic genetic deafness; Nonsyndromic genetic deafness
Identifiers:: MONDO: MONDO:0019497; MedGen: C5680182; Orphanet: 87884

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solute carrier family 22 member 18 isoform X2 [Homo sapiens]
solute carrier family 22 member 18 isoform X2 [Homo sapiens]
gi|2462525610|ref|XP_054224954.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001427358	INGEBI, INGEBI / CONICET	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Likely pathogenic (Aug 4, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24158611, 30311386

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001427358

INGEBI, INGEBI / CONICET

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Likely pathogenic
(Aug 4, 2020)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
Caucasian	germline	yes	3	1	not provided	not provided	yes	clinical testing

Citations

PubMed

Identification of four novel connexin 26 mutations in non-syndromic deaf patients: genotype-phenotype analysis in moderate cases.

Dalamón V, Florencia Wernert M, Lotersztein V, Craig PO, Diamante RR, Barteik ME, Curet C, Paoli B, Mansilla E, Elgoyhen AB.

Mol Biol Rep. 2013 Dec;40(12):6945-55. doi: 10.1007/s11033-013-2814-x. Epub 2013 Oct 25.

PubMed [citation]

PMID:: 24158611

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

Details of each submission

From INGEBI, INGEBI / CONICET, SCV001427358.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	3	not provided	yes	clinical testing	PubMed (2)

Description

Based on ACMG/AMP guidelines and Hearing Loss Expert Panel specific criteria: The c.632G>A, p.(Cys211Tyr) variant is absent from population databases (gnomAD, GO-ESP, 1000 genomes) meeting PM2 criteria. It has been identified in trans with del(GJB6-D13S1830) variant in two siblings with moderate postlingual hearing loss. There was an unaffected brother who only carried the p.(Cys211Tyr) variant (PMID: 24158611; PM3, PP1_Supporting). Finally, computational evidence predicted a pathogenic effect of the mutation to the protein (REVEL: 0.970) applying to PP3. In summary, this variant meets criteria to be classified as likely pathogenic for autosomal recessive non-syndromic hearing loss (PM2, PM3, PP1_Supporting and PP3).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	blood	not provided		3	not provided	1	not provided

Last Updated: Sep 29, 2024

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