VCV000550195.9 - ClinVar

NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)

Variation ID: 550195 Accession: VCV000550195.9

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q12.11 13: 20189488 (GRCh38) [ NCBI UCSC ] 13: 20763627 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Aug 5, 2018	Feb 14, 2024	Dec 15, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004004.6:c.94C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_003995.2:p.Arg32Ser	missense
NC_000013.11:g.20189488G>T
NC_000013.10:g.20763627G>T
NG_008358.1:g.8488C>A
LRG_1350:g.8488C>A
LRG_1350t1:c.94C>A	LRG_1350p1:p.Arg32Ser

... more HGVS ... less HGVS

Protein change

R32S

Other names

Canonical SPDI

NC_000013.11:20189487:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs371024165 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GJB2		Dosage sensitivity unlikely	No evidence available	GRCh38 GRCh37	570	637

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal recessive nonsyndromic hearing loss 1A	Likely pathogenic (1)	criteria provided, single submitter	Dec 21, 2016	RCV000664869.1
Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Autosomal dominant nonsyndromic hearing loss 3A Autosomal recessive nonsyndromic hearing loss 1A Ichthyosis, hystrix-like, with hearing loss Knuckle pads, deafness AND leukonychia syndrome Mutilating keratoderma Palmoplantar keratoderma-deafness syndrome X-linked mixed hearing loss with perilymphatic gusher	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762905.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 15, 2023	RCV001861739.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Dec 21, 2016)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Autosomal recessive nonsyndromic hearing loss 1A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000788891.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 21112098‚ 24774219‚ 26553399
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mutilating keratoderma Autosomal dominant keratitis-ichthyosis-hearing loss syndrome Palmoplantar keratoderma-deafness syndrome Knuckle pads, deafness AND leukonychia syndrome Autosomal recessive nonsyndromic hearing loss 1A X-linked mixed hearing loss with perilymphatic gusher Autosomal dominant nonsyndromic hearing loss 3A Ichthyosis, hystrix-like, with hearing loss Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893315.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Sep 08, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV004034736.1 First in ClinVar: Sep 16, 2023 Last updated: Sep 16, 2023	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31370293, … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31370293, 21112098, 26553399, 24774219, 33753912) (less)
Pathogenic (Dec 15, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002243770.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024	Publications: PubMed (9) PubMed: 21112098‚ 24774219‚ 26553399‚ 31370293‚ 11102979‚ 19371219‚ 21465647‚ 26346709‚ 27045574 Comment: This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 32 of the GJB2 protein (p.Arg32Ser). … (more) This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 32 of the GJB2 protein (p.Arg32Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 21112098, 24774219, 26553399, 31370293). ClinVar contains an entry for this variant (Variation ID: 550195). 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 expected to disrupt GJB2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)

Comment:

This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 32 of the GJB2 protein (p.Arg32Ser). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individuals with autosomal recessive non-syndromic deafness (PMID: 21112098, 24774219, 26553399, 31370293). ClinVar contains an entry for this variant (Variation ID: 550195). 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 expected to disrupt GJB2 protein function with a positive predictive value of 95%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg32 amino acid residue in GJB2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11102979, 19371219, 21465647, 26346709, 27045574). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Identification of Main Genetic Causes Responsible for Non-Syndromic Hearing Loss in a Peruvian Population.	Figueroa-Ildefonso E	Genes	2019	PMID: 31370293
Compound heterozygous GJB2 mutations associated to a consanguineous Han family with autosomal recessive non-syndromic hearing loss.	Xia H	Acta oto-laryngologica	2016	PMID: 27045574
A Mayan founder mutation is a common cause of deafness in Guatemala.	Carranza C	Clinical genetics	2016	PMID: 26346709
Two novel compound heterozygous families with a trimutation in the GJB2 gene causing sensorineural hearing loss.	Martínez-Saucedo M	International journal of pediatric otorhinolaryngology	2015	PMID: 26553399
Particular distribution of the GJB2/GJB6 gene mutations in Mexican population with hearing impairment.	Loeza-Becerra F	International journal of pediatric otorhinolaryngology	2014	PMID: 24774219
Vestibular dysfunction in DFNB1 deafness.	Dodson KM	American journal of medical genetics. Part A	2011	PMID: 21465647
Prevalence of GJB2 causing recessive profound non-syndromic deafness in Japanese children.	Hayashi C	International journal of pediatric otorhinolaryngology	2011	PMID: 21112098
Analysis of the GJB2 and GJB6 genes in Italian patients with nonsyndromic hearing loss: frequencies, novel mutations, genotypes, and degree of hearing loss.	Primignani P	Genetic testing and molecular biomarkers	2009	PMID: 19371219
Genetic testing for hereditary hearing loss: connexin 26 (GJB2) allele variants and two novel deafness-causing mutations (R32C and 645-648delTAGA).	Prasad S	Human mutation	2000	PMID: 11102979

Text-mined citations for rs371024165 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_004004.6(GJB2):c.94C>A (p.Arg32Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs371024165 ...