VCV000505242.11 - ClinVar

NM_001080476.3(GRXCR1):c.784C>T (p.Arg262Ter)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic

3 out of 3 submissions contributed to this 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.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001080476.3(GRXCR1):c.784C>T (p.Arg262Ter)

Variation ID: 505242 Accession: VCV000505242.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 4p13 4: 43030451 (GRCh38) [ NCBI UCSC ] 4: 43032468 (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	Apr 9, 2018	Feb 15, 2026	Oct 5, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_001080476.3:c.784C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001073945.1:p.Arg262Ter	nonsense
NC_000004.12:g.43030451C>T
NC_000004.11:g.43032468C>T
NG_027718.1:g.142186C>T

Protein change

R262*

Other names

Canonical SPDI

NC_000004.12:43030450:C:T

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.

The Genome Aggregation Database (gnomAD) 0.00001

Exome Aggregation Consortium (ExAC) 0.00002

The Genome Aggregation Database (gnomAD) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Trans-Omics for Precision Medicine (TOPMed) 0.00003

Links

ClinGen: CA2904532 dbSNP: rs761349153 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.
GRXCR1		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	149	165

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.
Rare genetic deafness	Likely pathogenic (1)	criteria provided, single submitter	Aug 18, 2016	RCV000615962.4
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jan 6, 2025	RCV001860247.6
Monogenic hearing loss	Likely pathogenic (1)	criteria provided, single submitter	Oct 5, 2025	RCV006261748.1

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.	Expand all rows Collapse all rows 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 (Aug 18, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Rare genetic deafness (Autosomal recessive inheritance)	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000712390.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018	Publications: PubMed (1) PubMed: 25802247 Comment: show The p.Arg262X variant in GRXCR1 has been reported in one individual with hearing loss and segregated with disease in one affected relative (Mori 2015). Both ind ividuals also harbored a second GRXCR1 variant on the remaining copy of the gene . This variant has been identified in 2/8614 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs761349153 ). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 262, which is locate d in the last exon and is more likely to escape nonsense mediated decay (NMD) an d result in a truncated protein. The GRXCR1 gene contains four exons, and the l ast exon is highly conserved; however, truncating variants have not been reporte d 3' of the p.Arg262X variant. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Arg262X variant is likel y pathogenic for autosomal recessive hearing loss. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 2

Likely pathogenic (Oct 05, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024 v1.2)	Monogenic hearing loss	Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub Accession: SCV007113801.1 First in ClinVar: Dec 07, 2025 Last updated: Dec 07, 2025	Comment: show PM2_moderate, PVS1_strong, PM3_supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Likely pathogenic (Jan 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002307881.5 First in ClinVar: Mar 28, 2022 Last updated: Feb 15, 2026	Publications: PubMed (2) PubMed: 25802247‚ 31389194 Comment: show This sequence change creates a premature translational stop signal (p.Arg262*) in the GRXCR1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the GRXCR1 protein. This variant is present in population databases (rs761349153, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with deafness (PMID: 25802247, 31389194). ClinVar contains an entry for this variant (Variation ID: 505242). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Comment:

The p.Arg262X variant in GRXCR1 has been reported in one individual with hearing loss and segregated with disease in one affected relative (Mori 2015). Both ind ividuals also harbored a second GRXCR1 variant on the remaining copy of the gene . This variant has been identified in 2/8614 East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs761349153 ). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 262, which is locate d in the last exon and is more likely to escape nonsense mediated decay (NMD) an d result in a truncated protein. The GRXCR1 gene contains four exons, and the l ast exon is highly conserved; however, truncating variants have not been reporte d 3' of the p.Arg262X variant. In summary, although additional studies are requi red to fully establish its clinical significance, the p.Arg262X variant is likel y pathogenic for autosomal recessive hearing loss.

Comment:

This sequence change creates a premature translational stop signal (p.Arg262*) in the GRXCR1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acid(s) of the GRXCR1 protein. This variant is present in population databases (rs761349153, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with deafness (PMID: 25802247, 31389194). ClinVar contains an entry for this variant (Variation ID: 505242). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Sequence variants in genes causing nonsyndromic hearing loss in a Pakistani cohort.	Khan A	Molecular genetics & genomic medicine	2019	PMID: 31389194
Novel mutation in GRXCR1 at DFNB25 lead to progressive hearing loss and dizziness.	Mori K	The Annals of otology, rhinology, and laryngology	2015	PMID: 25802247

Text-mined citations for rs761349153 ...

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 Feb 15, 2026