NM_206933.4(USH2A):c.10073G>A (p.Cys3358Tyr) AND Usher syndrome type 2A

Germline classification:: Pathogenic/Likely pathogenic (9 submissions)
Last evaluated:: Aug 5, 2025
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:: RCV000190637.20

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]

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
SCV000536900	Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq	no assertion criteria provided	Likely pathogenic (Jul 19, 2016)	paternal	research	PubMed (4) [See all records that cite these PMIDs] 20507924, 22004887, 25097241, 25472526
SCV000538073	Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 27, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001193786	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 (7) [See all records that cite these PMIDs] 22004887, 22334370, 26667666, 25472526, 25097241, 25649381, 20507924 Citation Link,
SCV001520105	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 30, 2019)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 25097241, 20507924, 25472526, 22004887, 25741868
SCV002011779	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	no assertion criteria provided	Likely pathogenic (Aug 25, 2021)	germline	clinical testing
SCV002557348	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22004887, 25649381, 25741868
SCV004182599	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007100162	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 12, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV007530063	Natera, Inc.	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Pathogenic (Aug 5, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	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	paternal	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	yes	not provided	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

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

NGS-based Molecular diagnosis of 105 eyeGENE(®) probands with Retinitis Pigmentosa.

Ge Z, Bowles K, Goetz K, Scholl HP, Wang F, Wang X, Xu S, Wang K, Wang H, Chen R.

Sci Rep. 2015 Dec 15;5:18287. doi: 10.1038/srep18287.

PubMed [citation]

PMID:: 26667666
PMCID:: PMC4678898

See all PubMed Citations (9)

Details of each submission

From Division of Human Genetics, Children's Hospital of Philadelphia - CSER-PediSeq, SCV000536900.1

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

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

From Knight Diagnostic Laboratories, Oregon Health and Sciences University - CSER-NextGen, SCV000538073.1

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

Description

The c.10073G>A (p.Cys3358Tyr) missense variant in the USH2A gene has been previously reported in several individuals affected with Usher Syndrome or Retinitis Pigmentosa. This allele was observed in 13 cases out of 914 affected alleles (Lenassi et al., 2015) and is significantly higher than the allele frequency in the ExAC database (13/121292). This variant is often seen in trans with other pathogenic variants (Garcia-Garcia et al., 2011; Le Quesne Stabej et al., 2012; Neveling et al., 2012; Lenassi et al., 2015). This c.10073G>A allele has been reported at low frequency, or is absent in other population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA). Multiple in silico algorithms predict this variant to have a deleterious effect GERP = 5.76; CADD = 22.4; PolyPhen = 1; SIFT = 0). Reputable diagnostic laboratories have reported this variant as either Likely Pathogenic or Pathogenic for either, Retinitis Pigmentosa or Usher Syndrome, Type 2A. Therefore, this collective evidence supports the classification of the c.10073G>A (p.Cys3358Tyr) as a recessive Likely Pathogenic variant for Usher syndrome, type IIA.

#	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 Myriad Genetics, Inc., SCV001193786.1

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

Description

NM_206933.2(USH2A):c.10073G>A(C3358Y) is classified as likely pathogenic in the context of USH2A-related disorders and is primarily associated with retinitis pigmentosa. Sources cited for classification include the following: PMID 22004887, 22334370, 26667666, 25472526, 25097241, 25649381 and 20507924. Classification of NM_206933.2(USH2A):c.10073G>A(C3358Y) 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 Baylor Genetics, SCV001520105.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 25097241, 20507924, 25472526, 22004887, ClinVar ID: 197932]

#	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 Clinical Genetics Laboratory, University Hospital Schleswig-Holstein, SCV002011779.1

#	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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557348.2

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

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 (MIM# 6138093). (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 tyrosine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 111 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) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with both Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (MIM# 6138093), and classified as both like pathogenic and pathogenic by diagnostic laboratories in Clinvar (PMID: 22004887, 25649381). (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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV004182599.1

#	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 Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare, SCV007100162.1

#	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	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Natera, Inc., SCV007530063.1

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

Description

The c.10073G>A variant in USH2A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 3358. This variant is rare in the general population with a frequency below the threshold expected for the associated phenotype(s). This variant has been observed in one or more individuals affected with the associated recessive disease, as either homozygous or compound heterozygous with a second variant (PMID: 29953849). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is 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

Last Updated: Jul 14, 2026

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