NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) AND Retinal dystrophy

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 15, 2021
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:: RCV000504814.13

Allele description [Variation Report for NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe)]

NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe)

Other names:

USH2A, CYS759PHE (rs80338902); NP_996816.3:p.(Cys759Phe)

HGVS:

NC_000001.11:g.216247118C>A
NG_009497.2:g.181331G>T
NM_007123.6:c.2276G>T
NM_206933.4:c.2276G>TMANE SELECT
NP_009054.5:p.Cys759Phe
NP_009054.6:p.Cys759Phe
NP_996816.3:p.Cys759Phe
NC_000001.10:g.216420460C>A
NG_009497.1:g.181279G>T
NM_007123.5:c.2276G>T
NM_206933.2(USH2A):c.2276G>T
NM_206933.2:c.2276G>T
NM_206933.3:c.2276G>T
O75445:p.Cys759Phe
c.2276G>T
p.(Cys759Phe)

Protein change:

C759F; CYS759PHE

Links:

UniProtKB: O75445#VAR_025775; OMIM: 608400.0006; dbSNP: rs80338902

NCBI 1000 Genomes Browser:

rs80338902

Molecular consequence:

NM_007123.6:c.2276G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.2276G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Retinal dystrophy
Synonyms:: Inherited retinal dystrophy
Identifiers:: MONDO: MONDO:0019118; MeSH: D058499; MedGen: C0854723; Human Phenotype Ontology: HP:0000556

Recent activity

Clear Turn Off Turn On

nsv526163 (1)
dbVar

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000598798	NIHR Bioresource Rare Diseases, University of Cambridge	no assertion criteria provided	Likely pathogenic (Jan 1, 2015)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 10775529, 28041643
SCV001239951	Blueprint Genetics	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Pathogenic (Jul 30, 2019)	germline	clinical testing	Citation Link,
SCV002761643	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 15, 2021)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 10775529, 12525556, 21151602, 29912909, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000598798

NIHR Bioresource Rare Diseases, University of Cambridge

no assertion criteria provided

Likely pathogenic
(Jan 1, 2015)

unknown

research

PubMed (2)
[See all records that cite these PMIDs]

SCV001239951

Blueprint Genetics

criteria provided, single submitter

(Blueprint Genetics Variant Classification Scheme)

Pathogenic
(Jul 30, 2019)

germline

clinical testing

Citation Link,

SCV002761643

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 15, 2021)

germline

clinical testing

PubMed (5)
[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
European	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss.

Rivolta C, Sweklo EA, Berson EL, Dryja TP.

Am J Hum Genet. 2000 Jun;66(6):1975-8. Epub 2000 Apr 20.

PubMed [citation]

PMID:: 10775529
PMCID:: PMC1378039

See all PubMed Citations (6)

Details of each submission

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV000598798.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Blueprint Genetics, SCV001239951.1

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

#	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 Genetics and Molecular Pathology, SA Pathology, SCV002761643.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The USH2A c.2276G>T variant is classified as Pathogenic (PS4, PM3_Strong, PP1, PP3) The USH2A c.2276G>T variant is a single nucleotide change in the USH2A gene, which is predicted to change the amino acid cysteine at position 759 in the protein to phenylalanine. The variant has been reported in probands with a clinical presentation of Retinal dystrophy (PS4). PMID: 29912909. This variant segregates with disease in multiple unrelated families with Usher syndrome type II and non-syndromic ARRP (Pérez-Carro et al., 2018, PMID:29912909, Rivolta et al., 2000, PMID:10775529, Bernal at al, 2003, PMID:12525556, Ávila-Fernández et al., 2010, PMID:21151602) (PP1). This variant has been detected in trans with a pathogenic variant for this recessive condition (PM3). Computational predictions support a deleterious effect on the gene or gene product (PP3). Cysteine at position 759 is highly conserved (PhyloP=5.53) located in the EGF-like, laminin domain. Substitution with Phenylalanine is a non-conservative change (Grantham Score =205). Computational analysis predicts this change is damaging (CADD=33, SIFT=Deleterious). The variant has been reported in dbSNP (rs80338902) and has been reported as Pathogenic/Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 2356).

#	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

Last Updated: Oct 13, 2024

ClinVar

Relating variation to medicine