NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr) AND Retinitis pigmentosa

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jul 24, 2023
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:: RCV000505000.13

Allele description [Variation Report for NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr)]

NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr)

Other names:

NM_206933.2(USH2A):c.10073G>A(p.Cys3358Tyr); NP_996816.3:p.(Cys3358Tyr)

HGVS:

NC_000001.11:g.215790168C>T
NG_009497.2:g.638281G>A
NM_206933.4:c.10073G>AMANE SELECT
NP_996816.3:p.Cys3358Tyr
NC_000001.10:g.215963510C>T
NG_009497.1:g.638229G>A
NM_206933.2:c.10073G>A
NM_206933.3:c.10073G>A
O75445:p.Cys3358Tyr

Protein change:

C3358Y

Links:

UniProtKB: O75445#VAR_068356; dbSNP: rs148660051

Molecular consequence:

NM_206933.4:c.10073G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Retinitis pigmentosa (RP)
Identifiers:: MONDO: MONDO:0019200; MeSH: D012174; MedGen: C0035334; Orphanet: 791; OMIM: 268000; OMIM: PS268000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000245680	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Pathogenic (Mar 29, 2021)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 22004887, 21151602, 20507924, 22135276, 22334370, 25649381, 25999674, 25472526, 25097241, 28559085, 29953849, 24033266
SCV000598759	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] 20507924, 28041643
SCV001161345	Sharon lab, Hadassah-Hebrew University Medical Center	no assertion criteria provided	Likely pathogenic (Jun 23, 2019)	inherited	research
SCV001950390	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Apr 1, 2021)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 26667666, 25649381, 25472526, 25097241, 22135276, 22004887, 21151602, 20507924, 25741868, 34906470
SCV004030329	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 24, 2023)	germline	research	PubMed (2) [See all records that cite these PMIDs] 36909829, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	1	not provided	not provided	not provided	not provided	research, curation
not provided	germline	unknown	4	3	not provided	not provided	not provided	clinical testing
European	unknown	yes	6	not provided	not provided	6	not provided	research

Citations

PubMed

Next-generation genetic testing for retinitis pigmentosa.

Neveling K, Collin RW, Gilissen C, van Huet RA, Visser L, Kwint MP, Gijsen SJ, Zonneveld MN, Wieskamp N, de Ligt J, Siemiatkowska AM, Hoefsloot LH, Buckley MF, Kellner U, Branham KE, den Hollander AI, Hoischen A, Hoyng C, Klevering BJ, van den Born LI, Veltman JA, Cremers FP, et al.

Hum Mutat. 2012 Jun;33(6):963-72. doi: 10.1002/humu.22045. Epub 2012 Mar 19. Erratum in: Hum Mutat. 2013 Aug;34(8):1181.

PubMed [citation]

PMID:: 22334370
PMCID:: PMC3490376

The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice.

van Huet RA, Pierrache LH, Meester-Smoor MA, Klaver CC, van den Born LI, Hoyng CB, de Wijs IJ, Collin RW, Hoefsloot LH, Klevering BJ.

Mol Vis. 2015;21:461-76.

PubMed [citation]

PMID:: 25999674
PMCID:: PMC4415583

See all PubMed Citations (17)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000245680.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	4	not provided	not provided	clinical testing	PubMed (12)

Description

The p.Cys3358Tyr variant in USH2A has been reported in over 15 individuals with retinitis pigmentosa, with at least 9 of these individuals being compound heterozygous for a pathogenic variant on the remaining copy of USH2A (Calzetti 2018 PMID:29953849, Garcia-Garcia 2011 PMID:22004887, LeQuesne Stabej 2012 PMID:22135276, Lenassi 2015 PMID:25649381, McGee 2010 PMID:20507924, Neveling 2012 PMID:22334370, Stone 2018 PMID:28559085, van Huet 2015 PMID:25999674, Wang 2014 PMID:25097241, Zhao 2015 PMID:25472526, Avila-Fernandez 2010 PMID:21151602). Two of these individuals were reported to have features of atypical type 2 Usher syndrome, with a later onset hearing loss (Garcia-Garcia 2011 PMID:22004887, Lenassi 2015 PMID:25649381), and one was reported to have hearing loss though age of onset was not noted (Calzetti 2018 PMID:29953849). The variant has been identified in 98/128872 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa and/or atypical type 2 Usher syndrome, based on the previously reported individuals. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3.

#	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		4	not provided	3	not provided

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV000598759.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	1	not provided	not provided	research	PubMed (2)
2	European	1	not provided	not provided	research	PubMed (2)
3	European	1	not provided	not provided	research	PubMed (2)
4	European	1	not provided	not provided	research	PubMed (2)
5	European	1	not provided	not provided	research	PubMed (2)
6	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
2	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Sharon lab, Hadassah-Hebrew University Medical Center, SCV001161345.1

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

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

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001950390.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (10)

Description

The p.Cys3358Tyr variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

#	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 Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, SCV004030329.2

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

Description

Clinical significance based on ACMG v2.0

#	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

Last Updated: Jul 14, 2026

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