NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) AND not provided

Germline classification:: Pathogenic (11 submissions)
Last evaluated:: Jan 31, 2024
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:: RCV000239000.49

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]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

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
SCV000225954	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Oct 5, 2017)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 10775529, 10909849, 12525556, 14970843, 18641288, 22004887, 23591405, 24944099, 28041643 Citation Link,
SCV000297411	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Oct 31, 2015)	unknown	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV000616913	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 2, 2023)	germline	clinical testing	Citation Link,
SCV000931893	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10775529, 12525556, 15325563, 25649381, 25910913, 28041643, 28492532
SCV001248859	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2022)	germline	clinical testing	Citation Link,
SCV001446852	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001472509	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Oct 9, 2023)	germline	clinical testing	Citation Link,
SCV001807717	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001920751	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001967307	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV002020845	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	11	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	9	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Identification of novel USH2A mutations: implications for the structure of USH2A protein.

Dreyer B, Tranebjaerg L, Rosenberg T, Weston MD, Kimberling WJ, Nilssen O.

Eur J Hum Genet. 2000 Jul;8(7):500-6.

PubMed [citation]

PMID:: 10909849

Genetic analysis of 2299delG and C759F mutations (USH2A) in patients with visual and/or auditory impairments.

Aller E, Nájera C, Millán JM, Oltra JS, Pérez-Garrigues H, Vilela C, Navea A, Beneyto M.

Eur J Hum Genet. 2004 May;12(5):407-10.

PubMed [citation]

PMID:: 14970843

See all PubMed Citations (14)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000225954.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	11	not provided	not provided	clinical testing	PubMed (9)

#	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		11	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000297411.3

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000616913.6

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

Description

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: 25472526, 29588463, 33576794, 33105617, 12525556, 25097241, 20440071, 25823529, 30609409, 30245029, 30924848, 32483926, 31429209, 32531858, 25262649, 10775529, 25910913, 26764160, 25649381, 26969326, 22004887, 15325563, 29283788, 28678594, 30390570, 32581362, 25326637, 28838317, 30190494, 28559085, 32050993, 32176120, 29953849, 24963352, 29777677, 28041643, 30081015, 29431110, 30337596, 32036094, 14970843, 30096711, 28945494, 29912909, 34327195, 34426522, 33302505, 33089500, 32037395, 35836572, 34948090, 36051698, 36003347, 36034145, 36140798, 36011334, 35672333, 34599368, 34781295, 35266249, 31877679)

#	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 Invitae, SCV000931893.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 759 of the USH2A protein (p.Cys759Phe). This variant is present in population databases (rs80338902, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individuals with autosomal recessive isolated retinitis pigmentosa and USH2A-related disorders (PMID: 10775529, 12525556, 15325563, 25649381, 25910913, 28041643). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2356). 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 USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been classified 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

From CeGaT Center for Human Genetics Tuebingen, SCV001248859.21

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	9	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		9	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446852.1

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

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472509.2

#	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; p.Cys759Phe variant (rs80338902) is reported in the medical literature in the homozygous or compound heterozygous state in individuals with retinal disease (Bernal 2003, Carss 2017, Lenassi 2015, Seyedahmadi 2004) and is reported to segregate with disease (Rivolta 2000). The variant is reported to occur at an increased frequency compared to control individuals (Seyedahmadi 2004). However, the variant was also detected in two unaffected individuals in the homozygous state (Bernal 2003). The variant is reported as pathogenic or likely pathogenic for Usher-related disease by several sources in the ClinVar database (Variation ID: 2356); however, the variant was recently classified as a variant of uncertain significance for hearing loss based on an expert panel curation (Azaiez 2018). The variant is reported in the general population with an overall allele frequency of 0.097% (273/282,114 alleles) in the Genome Aggregation Database. The cysteine at codon 759 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Azaiez H et al. Genomic Landscape and Mutational Signatures of Deafness-Associated Genes. Am J Hum Genet. 2018 Oct 4;103(4):484-497. Bernal S et al. Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation. J Med Genet. 2003 Jan;40(1):e8. Carss KJ et al. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017 Jan 5;100(1):75-90. Lenassi E et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27 Rivolta C et al. Missense mutation in the USH2A gene: association with recessive retinitis pigmentosa without hearing loss. Am J Hum Genet. 2000 Jun;66(6):1975-8. Seyedahmadi BJ et al. Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa. Exp Eye Res. 2004 Aug;79(2):167-73.

#	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 Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001807717.1

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001920751.1

#	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 Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001967307.1

#	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 Revvity Omics, Revvity, SCV002020845.3

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

#	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: Jun 2, 2024

Relating variation to medicine