NM_004004.6(GJB2):c.663G>C (p.Lys221Asn) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Apr 18, 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:: RCV001778681.7

Allele description [Variation Report for NM_004004.6(GJB2):c.663G>C (p.Lys221Asn)]

NM_004004.6(GJB2):c.663G>C (p.Lys221Asn)

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.663G>C (p.Lys221Asn)

HGVS:

NC_000013.11:g.20188919C>G
NG_008358.1:g.9057G>C
NM_004004.6:c.663G>CMANE SELECT
NP_003995.2:p.Lys221Asn
LRG_1350t1:c.663G>C
LRG_1350:g.9057G>C
LRG_1350p1:p.Lys221Asn
NC_000013.10:g.20763058C>G
NM_004004.5:c.663G>C
c.663G>C

Protein change:

K221N

Links:

dbSNP: rs375599392

NCBI 1000 Genomes Browser:

rs375599392

Molecular consequence:

NM_004004.6:c.663G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002015519	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 18, 2024)	germline	clinical testing	Citation Link,
SCV002218918	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 24, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25401782, 25555641, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002015519

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Apr 18, 2024)

germline

clinical testing

Citation Link,

SCV002218918

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 24, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

New and rare GJB2 alleles in patients with nonsyndromic sensorineural hearing impairment: a genotype/auditory phenotype correlation.

Stanghellini I, Genovese E, Palma S, Ravani A, Falcinelli C, Guarnaccia MC, Percesepe A.

Genet Test Mol Biomarkers. 2014 Dec;18(12):839-44. doi: 10.1089/gtmb.2014.0185.

PubMed [citation]

PMID:: 25401782

Finding mutation within non-coding region of GJB2 reveals its importance in genetic testing of hearing loss in Iranian population.

Kashef A, Nikzat N, Bazzazadegan N, Fattahi Z, Sabbagh-Kermani F, Taghdiri M, Azadeh B, Mojahedi F, Khoshaeen A, Habibi H, Najmabadi H, Kahrizi K.

Int J Pediatr Otorhinolaryngol. 2015 Feb;79(2):136-8. doi: 10.1016/j.ijporl.2014.11.024. Epub 2014 Dec 3.

PubMed [citation]

PMID:: 25555641

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV002015519.4

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

Description

Reported in the heterozygous state without a second variant in patients with sensorineural hearing loss in the published literature (PMID: 34515852, 25401782); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25388846, 25555641, 25401782, 34515852)

#	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, SCV002218918.2

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

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 221 of the GJB2 protein (p.Lys221Asn). This variant is present in population databases (rs375599392, gnomAD 0.008%). This missense change has been observed in individual(s) with GJB2-related conditions (PMID: 25401782, 25555641). ClinVar contains an entry for this variant (Variation ID: 44764). 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) performed at Invitae indicates that this missense variant is not expected to disrupt GJB2 protein function. 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

Last Updated: Oct 8, 2024

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