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NM_004004.6(GJB2):c.583A>G (p.Met195Val) AND Autosomal dominant nonsyndromic hearing loss 3A

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Sep 1, 2022
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:
RCV002283467.1

Allele description [Variation Report for NM_004004.6(GJB2):c.583A>G (p.Met195Val)]

NM_004004.6(GJB2):c.583A>G (p.Met195Val)

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.583A>G (p.Met195Val)
HGVS:
  • NC_000013.11:g.20188999T>C
  • NG_008358.1:g.8977A>G
  • NM_004004.6:c.583A>GMANE SELECT
  • NP_003995.2:p.Met195Val
  • LRG_1350t1:c.583A>G
  • LRG_1350:g.8977A>G
  • LRG_1350p1:p.Met195Val
  • NC_000013.10:g.20763138T>C
  • NC_000013.10:g.20763138T>C
  • NM_004004.5:c.583A>G
  • NM_004004.6(GJB2):c.583A>GMANE SELECT
Protein change:
M195V
Links:
dbSNP: rs532203068
NCBI 1000 Genomes Browser:
rs532203068
Molecular consequence:
  • NM_004004.6:c.583A>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Autosomal dominant nonsyndromic hearing loss 3A
Synonyms:
Deafness, autosomal dominant 3a
Identifiers:
MONDO: MONDO:0011103; MedGen: C2675750; Orphanet: 90635; OMIM: 601544

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV0025725183billion
criteria provided, single submitter

(ACMG Guidelines, 2015)		Pathogenic
(Sep 1, 2022) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot provided1not providedclinical testing

Citations

PubMed

The pathological effects of connexin 26 variants related to hearing loss by in silico and in vitro analysis.

Kim HR, Oh SK, Lee ES, Choi SY, Roh SE, Kim SJ, Tsukihara T, Lee KY, Jeon CJ, Kim UK.

Hum Genet. 2016 Mar;135(3):287-98. doi: 10.1007/s00439-015-1625-7. Epub 2016 Jan 9.

PubMed [citation]
PMID:
26749107

Prevalence of GJB2 (connexin-26) and GJB6 (connexin-30) mutations in a cohort of 300 Brazilian hearing-impaired individuals: implications for diagnosis and genetic counseling.

Batissoco AC, Abreu-Silva RS, Braga MC, Lezirovitz K, Della-Rosa V, Alfredo T Jr, Otto PA, Mingroni-Netto RC.

Ear Hear. 2009 Feb;30(1):1-7. doi: 10.1097/AUD.0b013e31819144ad.

PubMed [citation]
PMID:
19125024
See all PubMed Citations (8)

Details of each submission

From 3billion, SCV002572518.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (8)

Description

The variant is observed at an allele frequency greater than expected for the associated disorder in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26749107). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000225375). The variant has been observed in at least four similarly affected unrelated individuals (PMID: 19125024, 19366456, 21366436, 23555729). A different missense change at the same codon (p.Met195Ile) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000438621 , VCV001334161 , VCV001479826). The variant is in trans with the other pathogenic variants (PMID: 19125024,24507663,30146550). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot provided1not providednot providednot provided

Last Updated: Nov 3, 2024