VCV000198318.15 - ClinVar

NM_206933.4(USH2A):c.11875_11876del (p.Gln3959fs)

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.

(12)

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_206933.4(USH2A):c.11875_11876del (p.Gln3959fs)

Variation ID: 198318 Accession: VCV000198318.15

Type and length

Microsatellite, 2 bp

Location

Cytogenetic: 1q41 1: 215728220-215728221 (GRCh38) [ NCBI UCSC ] 1: 215901562-215901563 (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	Jun 28, 2015	Jun 17, 2024	Mar 4, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.11875_11876del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Gln3959fs	frameshift
NM_206933.2:c.11875_11876del
NC_000001.11:g.215728221GT[1]
NC_000001.10:g.215901563GT[1]
NG_009497.2:g.700226CA[1]

... more HGVS ... less HGVS

Protein change

Q3959fs

Other names

Canonical SPDI

NC_000001.11:215728219:TGTGT:TGT

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

ClinGen: CA275365 dbSNP: rs779791079 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.
USH2A		-	-	GRCh38 GRCh37	7080	8575

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV000179599.11
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Jan 1, 2015	RCV000505154.1
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Mar 30, 2022	RCV000671027.2
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	May 22, 2018	RCV001073824.2
Usher syndrome type 2A	Likely pathogenic (2)	criteria provided, single submitter	Nov 4, 2023	RCV001826918.2
Retinitis pigmentosa 39	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Mar 4, 2024	RCV001376411.4

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.
Pathogenic (Oct 08, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000231869.5 First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015	Publications: PubMed (1) PubMed: 24944099 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A Number of individuals with the variant: 2 Sex: mixed
Pathogenic (Nov 26, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000795965.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 24944099
Pathogenic (Aug 30, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001168547.1 First in ClinVar: Mar 16, 2020 Last updated: Mar 16, 2020	Comment: The c.11875_11876delCA variant in the USH2A gene has been reported previously in association with Usher syndrome (Dreyer et al., 2008). The c.11875_11876delCA variant causes a … (more) The c.11875_11876delCA variant in the USH2A gene has been reported previously in association with Usher syndrome (Dreyer et al., 2008). The c.11875_11876delCA variant causes a frameshift starting with codon Glutamine 3959, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Gln3959AsnfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11875_11876delCA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.11875_11876delCA as a pathogenic variant. (less)
Pathogenic (May 22, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239388.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573539.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (1) PubMed: 18273898 Comment: The USH2A c.11875_11876del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The USH2A c.11875_11876del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic. (less)
Likely pathogenic (Mar 30, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002792884.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely pathogenic (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182061.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Likely pathogenic (Nov 04, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV004182062.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023
Pathogenic (Jan 11, 2024)	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: SCV001418176.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 10729113‚ 10909849‚ 20507924‚ 25649381‚ 28041643 Comment: This sequence change creates a premature translational stop signal (p.Gln3959Asnfs53) in the USH2A gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Gln3959Asnfs53) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs779791079, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of retinal dystrophy (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 198318). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Mar 04, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208129.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598771.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 18273898 Number of individuals with the variant: 1 Sex: male Ethnicity/Population group: European
Pathogenic (Sep 01, 2020)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV002088319.1 First in ClinVar: Feb 13, 2022 Last updated: Feb 13, 2022
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Comment:

The c.11875_11876delCA variant in the USH2A gene has been reported previously in association with Usher syndrome (Dreyer et al., 2008). The c.11875_11876delCA variant causes a frameshift starting with codon Glutamine 3959, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 53 of the new reading frame, denoted p.Gln3959AsnfsX53. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.11875_11876delCA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.11875_11876delCA as a pathogenic variant.

Comment:

The USH2A c.11875_11876del variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic.

Comment:

This sequence change creates a premature translational stop signal (p.Gln3959Asnfs*53) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs779791079, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with clinical features of retinal dystrophy (PMID: 28041643). ClinVar contains an entry for this variant (Variation ID: 198318). 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
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.	Lenassi E	European journal of human genetics : EJHG	2015	PMID: 25649381
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.	Baux D	Human mutation	2014	PMID: 24944099
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.	McGee TL	Journal of medical genetics	2010	PMID: 20507924
Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II.	Dreyer B	Human mutation	2008	PMID: 18273898
Identification of novel USH2A mutations: implications for the structure of USH2A protein.	Dreyer B	European journal of human genetics : EJHG	2000	PMID: 10909849
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.	Weston MD	American journal of human genetics	2000	PMID: 10729113
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-

Text-mined citations for rs779791079 ...

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_206933.4(USH2A):c.11875_11876del (p.Gln3959fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs779791079 ...