NM_206933.4(USH2A):c.2276G>T (p.Cys759Phe) AND Usher syndrome type 2A

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Mar 29, 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:: RCV000174625.32

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)

Name:: Usher syndrome type 2A
Synonyms:: USHER SYNDROME, TYPE IIA; RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF
Identifiers:: MONDO: MONDO:0010169; MedGen: C1848634; Orphanet: 231178; Orphanet: 886; OMIM: 276901

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001135564	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Likely pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001162882	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001194111	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2019))	Likely pathogenic (Dec 17, 2019)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24944099, 1968399, 18273898 Citation Link,
SCV001244815	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20301515, 25741868
SCV001737166	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 18, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002580572	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004100709	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 7, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004805852	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 29, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005051990	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2024)	germline	curation	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	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
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	clinical testing

Citations

PubMed

Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.

Baux D, Blanchet C, Hamel C, Meunier I, Larrieu L, Faugère V, Vaché C, Castorina P, Puech B, Bonneau D, Malcolm S, Claustres M, Roux AF.

Hum Mutat. 2014 Oct;35(10):1179-86. doi: 10.1002/humu.22608. Epub 2014 Jul 15.

PubMed [citation]

PMID:: 24944099

Allicin, a naturally occurring antibiotic from garlic, specifically inhibits acetyl-CoA synthetase.

Focke M, Feld A, Lichtenthaler K.

FEBS Lett. 1990 Feb 12;261(1):106-8.

PubMed [citation]

PMID:: 1968399

See all PubMed Citations (5)

Details of each submission

From Mendelics, SCV001135564.1

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

From Baylor Genetics, SCV001162882.1

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

From Myriad Genetics, Inc., SCV001194111.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

NM_206933.2(USH2A):c.2276G>T(C759F) is classified as likely pathogenic in the context of USH2A-related disorders and is associated with variable presentation of this disease. Sources cited for classification include the following: PMID 24944099, 1968399 and 18273898. Classification of NM_206933.2(USH2A):c.2276G>T(C759F) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV001244815.4

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (RP; MIM# 6138093). Null variants are associated with Usher syndrome while homozygous missense which lead to partially functional proteins typically cases non-syndromic RP (PMID: 20301515). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to phenylalanine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 273 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated Laminin EGF domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple Usher syndrome and RP individuals and classified as pathogenic by ClinGen’s hearing loss expert panel. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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-Nilou Lab, SCV001737166.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From MGZ Medical Genetics Center, SCV002580572.1

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

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004100709.2

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

Description

Criteria applied: PM3_VSTR,PP1_STR,PP3

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805852.1

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

From Laboratory of Medical Genetics, National & Kapodistrian University of Athens, SCV005051990.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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