NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) AND not provided
- Germline classification:
- Pathogenic (11 submissions)
- Last evaluated:
- Jul 1, 2024
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000239000.56
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)
This HGVS expression did not pass validation- 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:
- 21
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
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 | |
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, |
SCV000616913 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Pathogenic (May 9, 2024) | germline | clinical testing | |
SCV000931893 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jan 31, 2024) | germline | clinical testing | |
SCV001248859 | CeGaT Center for Human Genetics Tuebingen | criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) | Pathogenic (Jul 1, 2024) | germline | clinical testing | |
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 | |
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 | |
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
| 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
| 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 |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | unknown | 11 | not provided | not provided | not provided | not provided | clinical testing |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | yes | 10 | 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.
- PMID:
- 10909849
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.
- PMID:
- 14970843
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, SCV000616913.7
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
Published functional studies using a zebrafish knock-in model suggest a damaging effect with decreased expression of usherin and impaired visual function (PMID: 35672333); 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, 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, 34327195, 34426522, 33302505, 33089500, 32037395, 35836572, 34948090, 36051698, 36003347, 36034145, 36140798, 36011334, 34599368, 34781295, 35266249, 31877679, 35672333, 25823529, 29912909)
# | 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 Labcorp Genetics (formerly Invitae), Labcorp, 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, SCV001248859.25
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 10 | not provided | not provided | clinical testing | not provided |
Description
USH2A: PM3:Very Strong, PM2:Supporting, PS3:Supporting
# | 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 | 10 | 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: Oct 13, 2024