NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) AND USH2A-related disorder

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jun 14, 2016
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:: RCV000404009.18

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:: USH2A-related disorder
Synonyms:: USH2A-Related Disorders; USH2A-related condition
Identifiers:: MedGen: CN239332

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000354148	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification 20161018)	Pathogenic (Jun 14, 2016)	germline	clinical testing	PubMed (20) [See all records that cite these PMIDs] 10775529, 12525556, 21151602, 23591405, 25823529, 12427073, 12112664, 25649381, 25375654, 17405132, 14970843, 10909849, 15325563, 18641288, 21738395, 18273898, 22004887, 17085681, 25078356, 16098008 ICSL_Variant_Classification_20161018.pdf, Citation Link,
SCV002074994	GenomeConnect, ClinGen	no classification provided	not provided	unknown	phenotyping only
SCV004103099	PreventionGenetics, part of Exact Sciences	no assertion criteria provided	Pathogenic (Aug 21, 2024)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000354148

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification 20161018)

Pathogenic
(Jun 14, 2016)

germline

clinical testing

PubMed (20)
[See all records that cite these PMIDs]

ICSL_Variant_Classification_20161018.pdf,

Citation Link,

SCV002074994

GenomeConnect, ClinGen

no classification provided

not provided

unknown

phenotyping only

SCV004103099

PreventionGenetics, part of Exact Sciences

no assertion criteria provided

Pathogenic
(Aug 21, 2024)

germline

clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	phenotyping only

Citations

PubMed

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

Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation.

Bernal S, Ayuso C, Antiñolo G, Gimenez A, Borrego S, Trujillo MJ, Marcos I, Calaf M, Del Rio E, Baiget M.

J Med Genet. 2003 Jan;40(1):e8. No abstract available.

PubMed [citation]

PMID:: 12525556
PMCID:: PMC1735247

See all PubMed Citations (20)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000354148.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (20)

Description

The c.2276G>T (p.Cys759Phe) variant is a well described pathogenic variant for USH2A-related disorders. Across a selection of the available literature, the variant is reported in over 90 patients with retinitis pigmentosa and 40 patients with Usher syndrome (Rivolta et al. 2000; Dreyer et al. 2000; NÃ¡jera et al. 2002; Rivolta et al. 2002; Bernal et al. 2003; Aller et al. 2004; Seyedahmadi et al. 2004; Bernal et al. 2005; Baux et al. 2007; Dreyer et al. 2008; Sandberg et al. 2008; Ãvila-FernÃ¡ndez et al. 2010; Vozzi et al. 2011; GlÃ¶ckle et al. 2014; Blanco-Kelly et al. 2015; Lenassi et al. 2015). Among those with isolated retinitis pigmentosa, fifteen were found to be homozygous for the variant and 34 were identified as compound heterozygous for the variant. Furthermore, the p.Cys759Phe variant has been found to cosegregate with disease in multiple families (Bernal et al. 2003; Ãvila-FernÃ¡ndez et al. 2010). The variant was identified in a heterozygous state in eight of 3400 controls, and is reported at a frequency of 0.00209 in the European American population of the Exome Sequencing Project. The Cys759 residue occurs in a laminin-type epidermal growth factor-like domain. The p.Cys759Phe variant is predicted to disrupt disulfide bond formation and lead to abnormal protein folding (Dreyer et al. 2000; Baux et al. 2007). Based on the collective evidence, the p.Cys759Phe variant is classified as pathogenic for USH2A-related disorders.

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

From GenomeConnect, ClinGen, SCV002074994.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	phenotyping only	not provided

Description

Variant interpreted as Likely pathogenic and reported on 05-24-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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

From PreventionGenetics, part of Exact Sciences, SCV004103099.3

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

Description

The USH2A c.2276G>T variant is predicted to result in the amino acid substitution p.Cys759Phe. This variant has been reported many times in individuals with autosomal recessive Usher syndrome or non-syndromic retinitis pigmentosa (see for examples Rivolta et al. 2000. PubMed ID: 10775529; Aller et al. 2004. PubMed ID: 14970843; Garcia-Garcia et al. 2011. PubMed ID: 22004887). Several other missense variants occurring within amino acids 761 to 768 of USH2A have been reported as causative for Usher syndrome type 2, suggesting that this protein domain plays an important functional role (Bernal et al. 2003. PubMed ID: 12525556; Glöckle et al. 2014. PubMed ID: 23591405; Piearrche et al. 2016. PubMed ID: 26927203). This variant is reported in 0.20% of alleles in individuals of Latino descent in gnomAD. This variant has been interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/2356/). This variant is interpreted as pathogenic.

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

Last Updated: Nov 10, 2024

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