VCV000002359.81 - ClinVar

NM_206933.4(USH2A):c.1256G>T (p.Cys419Phe)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic
Pathogenic (19)

19 out of 28 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.1256G>T (p.Cys419Phe)

Variation ID: 2359 Accession: VCV000002359.81

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 216324240 (GRCh38) [ NCBI UCSC ] 1: 216497582 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jun 8, 2016	Jul 27, 2026	Jan 1, 2026

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.1256G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Cys419Phe	missense
NM_007123.6:c.1256G>T	NP_009054.6:p.Cys419Phe	missense
NC_000001.11:g.216324240C>A
NC_000001.10:g.216497582C>A
NG_009497.2:g.104209G>T
	O75445:p.Cys419Phe

... more HGVS ... less HGVS

Protein change

C419F

Other names

Canonical SPDI

NC_000001.11:216324239:C:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00005

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD) 0.00007

The Genome Aggregation Database (gnomAD) 0.00008

Links

OMIM: 608400.0009 dbSNP: rs121912600 ClinGen: CA252239 UniProtKB: O75445#VAR_025767 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
USH2A		Gene associated with autosomal recessive phenotype	Not yet evaluated	GRCh38 GRCh37	8088	9803

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Usher syndrome type 2A	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Aug 15, 2025	RCV000002453.20
Usher syndrome	Pathogenic (2)	criteria provided, single submitter	Dec 9, 2019	RCV000504809.6
not provided	Pathogenic (8)	criteria provided, multiple submitters, no conflicts	Jan 1, 2026	RCV000224697.59
Rare genetic deafness	Pathogenic (1)	criteria provided, single submitter	Oct 28, 2010	RCV000824795.5
Retinitis pigmentosa 39	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Dec 9, 2025	RCV000984315.8
Retinal dystrophy	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 1, 2020	RCV001074823.4
USH2A-related disorder	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 28, 2017	RCV000778222.6
Retinitis pigmentosa 39 Usher syndrome type 2A	Pathogenic (1)	criteria provided, single submitter	May 19, 2024	RCV002482817.3
Autosomal recessive USH2A-related disorders	Pathogenic (1)	criteria provided, single submitter	Oct 22, 2025	RCV006635408.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jan 12, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000281626.1 First in ClinVar: Jun 08, 2016 Last updated: Jun 08, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Platform type: Sequencing Platform name: Illumina

Pathogenic (Apr 28, 2017) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	USH2A-Related Disorders	Illumina Laboratory Services, Illumina Accession: SCV000914388.1 First in ClinVar: May 27, 2019 Last updated: May 27, 2019	Publications: PubMed (11) PubMed: 10729113‚ 15015129‚ 15241801‚ 15325563‚ 16963483‚ 18641288‚ 22135276‚ 22334370‚ 24265693‚ 24498627‚ 25999674 Comment: show Across a selection of the available literature, the USH2A c.1256G>T (p.Cys419Phe) missense variant has been identified in a homozygous state in two patients with Usher syndrome, in a compound heterozygous state in 13 patients of whom ten were diagnosed with Usher syndrome and three with retinitis pigmentosa (RP), and in a heterozygous state in 16 patients of whom ten were diagnosed with Usher syndrome and six with RP (Weston et al. 2000; Van Wijk et al. 2004; Seyedahmadi et al. 2004; Sandberg et al. 2008; Neveling et al. 2012; Le Quesne Stabe et al. 2012; Eisenberger et al. 2013; Besnard et al. 2014; Cremers et al. 2014; Pennings et al. 2004; Van Huet et al. 2015). The p.Cys419Phe variant is a possible Dutch founder variant as deduced by haplotype analysis by Pennings et al. (2004). The p.Cys419Phe variant was absent in at least 1000 controls and is reported at a frequency of 0.000093 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Cys419Phe variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 01, 2020) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinal dystrophy	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005072652.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (19) PubMed: 10729113‚ 22334370‚ 24265693‚ 28559085‚ 28761320‚ 31964843‚ 31980526‚ 32037395‚ 32176120‚ 32853555‚ 33360097‚ 33576794‚ 33749171‚ 34758253‚ 34781295‚ 35266249‚ 36011334‚ 36284670‚ 36819107 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 19, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Usher syndrome type 2A Retinitis pigmentosa 39 Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Fulgent Genetics, Fulgent Genetics Accession: SCV002780180.2 First in ClinVar: Dec 31, 2022 Last updated: Jan 25, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 21, 2016) C Contributing to aggregate classification	criteria provided, single submitter (EGL Classification Definitions 2015)	not provided	Eurofins Ntd Llc (ga) Accession: SCV000232370.6 First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025	Publications: PubMed (6) PubMed: 10729113‚ 15015129‚ 15241801‚ 22334370‚ 24265693‚ 25649381 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 8 Zygosity: 1 Homozygote, 7 Single Heterozygotes Sex: mixed

Pathogenic (Nov 06, 2025) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000583303.10 First in ClinVar: Jun 08, 2016 Last updated: Nov 15, 2025	Comment: show 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: 24944099, 22334370, 33576794, 32853555, 34758253, 24265693, 10729113, 15043528, 22135276, 28559085, 31980526, 32176120, 33360097, 31964843, 33749171, 34906470, 32037395, 36011334, 36284670, 34781295, 35266249, 28761320, 36819107, 20301515, 37237007, 25999674, 28041643, 18641288, 24498627, 16963483, 15015129, 15325563, 37108761, 25649381, 38219857) (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Dec 31, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001223238.7 First in ClinVar: Apr 15, 2020 Last updated: Feb 15, 2026	Publications: PubMed (8) PubMed: 10729113‚ 15043528‚ 15241801‚ 22334370‚ 24265693‚ 24498627‚ 28041643‚ 28559085 Comment: show This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 419 of the USH2A protein (p.Cys419Phe). This variant is present in population databases (rs121912600, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10729113, 15043528, 15241801, 22334370, 24265693, 24498627, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Dutch ancestry (PMID: 15241801). ClinVar contains an entry for this variant (Variation ID: 2359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 22, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Variantyx Assertion Criteria 2022)	Autosomal recessive USH2A-related disorders (Autosomal recessive inheritance)	Variantyx, Inc. Accession: SCV007520084.1 First in ClinVar: Mar 28, 2026 Last updated: Mar 28, 2026	Publications: PubMed (6) PubMed: 10729113‚ 15015129‚ 15325563‚ 16963483‚ 18641288‚ 22334370 Comment: show This is a nonsynonymous variant in the USH2A gene (OMIM: 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. This variant has been identified in the homozygous or compound heterozygous state in multiple unrelated affected individuals reported in the published literature (PMID: 16963483, 10729113, 15015129, 15325563, 18641288, 22334370) (PM3). The frequency of this variant in affected individuals is significantly increased compared to controls (PMID:10729113)(PS4). Mreoever, an alternate amino acid change at this position (p.Cys419Arg) has been previously reported in similarly affected individuals, which suggests that this residue is biologically important (PM5_Supporting). Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.608). This variant has a 0.0125% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the evidence, this variant is classified as pathogenic for autosomal recessive USH2A-related disorders. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 15, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Natera Variant Classification Schema (03/2026))	Usher syndrome type 2A	Natera, Inc. Accession: SCV001457324.2 First in ClinVar: Jan 02, 2021 Last updated: Apr 04, 2026	Publications: PubMed (2) PubMed: 22135276‚ 27460420 Comment: show The c.1256G>T variant in USH2A is a missense variant predicted to cause substitution of cysteine to phenylalanine at amino acid 419. 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: 22135276, 27460420). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Oct 28, 2010) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Rare genetic deafness	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000065420.6 First in ClinVar: May 03, 2013 Last updated: Aug 26, 2019	Publications: PubMed (3) PubMed: 10729113‚ 15241801‚ 15325563 Comment: show The Cys419Phe variant in USH2A has been reported in 16/246 probands with Usher s yndrome Type 2 and was absent from 380 control chromosomes (p<0.0001, Weston 200 0, Pennings 2004, Seyedahmadi 2004). Many of these probands were homozygous or c ompound heterozygous. In addition, this variant is thought to be a founder mutat ion in the Dutch population (Pennings 2004). In summary, this variant meets our criteria to be classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Pathogenic (Jul 17, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme)	Retinal dystrophy	Blueprint Genetics Accession: SCV001240423.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	USH2A-Related Disorders	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill Study: NSIGHT-NC NEXUS Accession: SCV001251480.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (8) PubMed: 10729113‚ 15015129‚ 15241801‚ 15325563‚ 20301515‚ 22135276‚ 24944099‚ 25999674 Comment: show USH2A c.1256G>T (p.C419F) has been described as a pathogenic variant and has been reported in the homozygous or compound heterozygous state in multiple individuals with Usher syndrome type IIA and nonsyndromic retinitis pigmentosa (PMID: 15015129; 15241801;15325563; 10729113; 22135276; 24944099; 25999674). (less) Observation: 1 Collection method: research Allele origin: paternal Affected status: yes more Observation 1 Collection method: research Allele origin: paternal Affected status: yes Number of individuals with the variant: 1 Platform type: exome sequencing

Pathogenic (Dec 09, 2019) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Usher syndrome	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001362170.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Publications: PubMed (4) PubMed: 10729113‚ 22334370‚ 24265693‚ 28559085 Comment: show Variant summary: USH2A c.1256G>T (p.Cys419Phe) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250184 control chromosomes. c.1256G>T has been reported in the literature in multiple individuals affected with Usher syndrome and/or Retinitis Pigmentosa (example, Weston_2000, Neveling_2012, Eisenberger_2013, Stone_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 08, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinitis pigmentosa 39	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573447.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (10) PubMed: 10729113‚ 15015129‚ 15241801‚ 16963483‚ 18641288‚ 22135276‚ 24265693‚ 24498627‚ 25649381‚ 25999674 Comment: show The USH2A c.1256G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. (less) Observation: 1 Collection method: research Allele origin: germline Affected status: yes Observation 1 Collection method: research Allele origin: germline Affected status: yes

Pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinitis pigmentosa 39	Genome-Nilou Lab Accession: SCV004182892.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Nov 04, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Usher syndrome type 2A	Genome-Nilou Lab Accession: SCV004182893.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: no Observation 1 Collection method: clinical testing Allele origin: germline Affected status: no

Pathogenic (Mar 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinitis pigmentosa 39	Baylor Genetics Accession: SCV004207721.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Dec 09, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Retinitis pigmentosa 39	3billion Accession: SCV007608711.1 First in ClinVar: Jun 20, 2026 Last updated: Jun 20, 2026	Publications: PubMed (3) PubMed: 10729113‚ 33749171‚ 36011334 Comment: show The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.88 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002359 /PMID: 10729113). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33749171, 36011334). A different missense change at the same codon (p.Cys419Arg) has been reported to be associated with USH2A-related disorder (ClinVar ID: VCV001913735). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Platform type: exome sequencing

Pathogenic (Jan 01, 2026) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001248863.39 First in ClinVar: May 09, 2020 Last updated: Jul 27, 2026	Comment: show USH2A: PM3:Very Strong, PM2, PM5 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 2

Pathogenic (Sep 01, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Usher syndrome type 2A	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Accession: SCV000804732.2 First in ClinVar: Sep 10, 2018 Last updated: Sep 10, 2018	Observation: 2 Observation 1 Collection method: clinical testing Allele origin: inherited Affected status: yes Number of individuals with the variant: 1 Observation 2 Collection method: clinical testing Allele origin: unknown Affected status: yes Number of individuals with the variant: 1

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics, Academic Medical Center Study: VKGL Data-share Consensus Accession: SCV001921479.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Study: VKGL Data-share Consensus Accession: SCV001958308.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Study: VKGL Data-share Consensus Accession: SCV001968070.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Feb 08, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Usher syndrome type 2A	Counsyl Accession: SCV001132499.2 First in ClinVar: Dec 23, 2019 Last updated: Jun 29, 2025	Publications: PubMed (3) PubMed: 10729113‚ 15241801‚ 22135276 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Feb 08, 2017) N Not contributing to aggregate classification	no assertion criteria provided	Retinitis pigmentosa 39	Counsyl Accession: SCV001132500.2 First in ClinVar: Dec 23, 2019 Last updated: Jun 29, 2025	Publications: PubMed (3) PubMed: 10729113‚ 15241801‚ 22135276 Comment: show This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Apr 01, 2004) N Not contributing to aggregate classification	no assertion criteria provided	USHER SYNDROME, TYPE IIA	OMIM Accession: SCV000022611.3 First in ClinVar: Apr 04, 2013 Last updated: Sep 10, 2018	Publications: PubMed (1) PubMed: 15015129 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided Comment on evidence: For discussion of the cys419-to-phe (C419F) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa … (more) For discussion of the cys419-to-phe (C419F) mutation in the USH2A gene that was found in compound heterozygous state in patients with Usher syndrome type IIa (USH2A; 276901) by van Wijk et al. (2004), see 608400.0007. (less)

Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided (ACGS Guidelines, 2016)	Usher syndrome type 2A	Genomics England Pilot Project, Genomics England Accession: SCV001760023.1 First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Jan 01, 2015) N Not contributing to aggregate classification	Flagged submission flagged submission Reason: Older and outlier claim with insufficient supporting evidence Source: ClinGen	Usher syndrome, type 2D	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598775.3 First in ClinVar: Sep 09, 2017 Last updated: Apr 13, 2025	Publications: PubMed (2) PubMed: 10729113‚ 28041643 Observation: 1 Collection method: research Allele origin: unknown Affected status: yes more Observation 1 Collection method: research Allele origin: unknown Affected status: yes Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European Platform type: Whole Genome Sequencing

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Comment:

Across a selection of the available literature, the USH2A c.1256G>T (p.Cys419Phe) missense variant has been identified in a homozygous state in two patients with Usher syndrome, in a compound heterozygous state in 13 patients of whom ten were diagnosed with Usher syndrome and three with retinitis pigmentosa (RP), and in a heterozygous state in 16 patients of whom ten were diagnosed with Usher syndrome and six with RP (Weston et al. 2000; Van Wijk et al. 2004; Seyedahmadi et al. 2004; Sandberg et al. 2008; Neveling et al. 2012; Le Quesne Stabe et al. 2012; Eisenberger et al. 2013; Besnard et al. 2014; Cremers et al. 2014; Pennings et al. 2004; Van Huet et al. 2015). The p.Cys419Phe variant is a possible Dutch founder variant as deduced by haplotype analysis by Pennings et al. (2004). The p.Cys419Phe variant was absent in at least 1000 controls and is reported at a frequency of 0.000093 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Cys419Phe variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

Comment:

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: 24944099, 22334370, 33576794, 32853555, 34758253, 24265693, 10729113, 15043528, 22135276, 28559085, 31980526, 32176120, 33360097, 31964843, 33749171, 34906470, 32037395, 36011334, 36284670, 34781295, 35266249, 28761320, 36819107, 20301515, 37237007, 25999674, 28041643, 18641288, 24498627, 16963483, 15015129, 15325563, 37108761, 25649381, 38219857)

Comment:

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 419 of the USH2A protein (p.Cys419Phe). This variant is present in population databases (rs121912600, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10729113, 15043528, 15241801, 22334370, 24265693, 24498627, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Dutch ancestry (PMID: 15241801). ClinVar contains an entry for this variant (Variation ID: 2359). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.

Comment:

This is a nonsynonymous variant in the USH2A gene (OMIM: 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. This variant has been identified in the homozygous or compound heterozygous state in multiple unrelated affected individuals reported in the published literature (PMID: 16963483, 10729113, 15015129, 15325563, 18641288, 22334370) (PM3). The frequency of this variant in affected individuals is significantly increased compared to controls (PMID:10729113)(PS4). Mreoever, an alternate amino acid change at this position (p.Cys419Arg) has been previously reported in similarly affected individuals, which suggests that this residue is biologically important (PM5_Supporting). Computational algorithms produce conflicting evidence regarding the predicted functional impact of this variant (REVEL score: 0.608). This variant has a 0.0125% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/). Based on the evidence, this variant is classified as pathogenic for autosomal recessive USH2A-related disorders.

Comment:

The c.1256G>T variant in USH2A is a missense variant predicted to cause substitution of cysteine to phenylalanine at amino acid 419. 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: 22135276, 27460420). Computational prediction algorithms indicate this variant is likely to affect gene or protein function. Given the available evidence, this variant is classified as Pathogenic.

Comment:

The Cys419Phe variant in USH2A has been reported in 16/246 probands with Usher s yndrome Type 2 and was absent from 380 control chromosomes (p<0.0001, Weston 200 0, Pennings 2004, Seyedahmadi 2004). Many of these probands were homozygous or c ompound heterozygous. In addition, this variant is thought to be a founder mutat ion in the Dutch population (Pennings 2004). In summary, this variant meets our criteria to be classified as pathogenic.

Comment:

USH2A c.1256G>T (p.C419F) has been described as a pathogenic variant and has been reported in the homozygous or compound heterozygous state in multiple individuals with Usher syndrome type IIA and nonsyndromic retinitis pigmentosa (PMID: 15015129; 15241801;15325563; 10729113; 22135276; 24944099; 25999674).

Comment:

Variant summary: USH2A c.1256G>T (p.Cys419Phe) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250184 control chromosomes. c.1256G>T has been reported in the literature in multiple individuals affected with Usher syndrome and/or Retinitis Pigmentosa (example, Weston_2000, Neveling_2012, Eisenberger_2013, Stone_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The USH2A c.1256G>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS4, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v4.1.0 dataset (total allele frequency: 0.009%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.61 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.88 (> 0.75, sensitivity 0.96 and precision 0.92)]. The same nucleotide change resulting in the same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000002359 /PMID: 10729113). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 33749171, 36011334). A different missense change at the same codon (p.Cys419Arg) has been reported to be associated with USH2A-related disorder (ClinVar ID: VCV001913735). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.	Panneman DM	Frontiers in cell and developmental biology	2023	PMID: 36819107
Usher Syndrome Type II.	Adam MP	-	2023	PMID: 20301515
Identification of numerous novel disease-causing variants in patients with inherited retinal diseases, combining careful clinical-functional phenotyping with systematic, broad NGS panel-based genotyping.	Gupta PR	Molecular vision	2022	PMID: 36284670
Phenotypic and Genetic Characteristics in a Cohort of Patients with Usher Genes.	Feenstra HM	Genes	2022	PMID: 36011334
Tissue-specific genotype-phenotype correlations among USH2A-related disorders in the RUSH2A study.	Hufnagel RB	Human mutation	2022	PMID: 35266249
Spectral-Domain Optical Coherence Tomography Analysis in Syndromic and Nonsyndromic Forms of Retinitis Pigmentosa due to USH2A Genetic Variants.	Colombo L	Ophthalmic research	2022	PMID: 34781295
100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.	100,000 Genomes Project Pilot Investigators	The New England journal of medicine	2021	PMID: 34758253
Panel-based genetic testing for inherited retinal disease screening 176 genes.	Sheck LHN	Molecular genetics & genomic medicine	2021	PMID: 33749171
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.	Colombo L	Investigative ophthalmology & visual science	2021	PMID: 33576794
Generation of three induced pluripotent stem cell lines from a patient with Usher syndrome caused by biallelic c.949C > A and c.1256G > T mutations in the USH2A gene.	Zaw K	Stem cell research	2021	PMID: 33360097
Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project.	Roman TS	American journal of human genetics	2020	PMID: 32853555
Establishing Genotype-phenotype Correlation in USH2A-related Disorders to Personalize Audiological Surveillance and Rehabilitation.	Molina-Ramírez LP	Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology	2020	PMID: 32176120
Copy-number variation contributes 9% of pathogenicity in the inherited retinal degenerations.	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32037395
Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.	Hou YC	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31980526
Worldwide carrier frequency and genetic prevalence of autosomal recessive inherited retinal diseases.	Hanany M	Proceedings of the National Academy of Sciences of the United States of America	2020	PMID: 31964843
Next-generation sequencing to solve complex inherited retinal dystrophy: A case series of multiple genes contributing to disease in extended families.	Jones KD	Molecular vision	2017	PMID: 28761320
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.	Carss KJ	American journal of human genetics	2017	PMID: 28041643
An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients.	Bonnet C	European journal of human genetics : EJHG	2016	PMID: 27460420
The efficacy of microarray screening for autosomal recessive retinitis pigmentosa in routine clinical practice.	van Huet RA	Molecular vision	2015	PMID: 25999674
A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.	Lenassi E	European journal of human genetics : EJHG	2015	PMID: 25649381
Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.	Baux D	Human mutation	2014	PMID: 24944099
Experience of targeted Usher exome sequencing as a clinical test.	Besnard T	Molecular genetics & genomic medicine	2014	PMID: 24498627
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.	Eisenberger T	PloS one	2013	PMID: 24265693
Next-generation genetic testing for retinitis pigmentosa.	Neveling K	Human mutation	2012	PMID: 22334370
Comprehensive sequence analysis of nine Usher syndrome genes in the UK National Collaborative Usher Study.	Le Quesne Stabej P	Journal of medical genetics	2012	PMID: 22135276
Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.	Sandberg MA	Investigative ophthalmology & visual science	2008	PMID: 18641288
Development of a genotyping microarray for Usher syndrome.	Cremers FP	Journal of medical genetics	2007	PMID: 16963483
Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa.	Seyedahmadi BJ	Experimental eye research	2004	PMID: 15325563
USH2A mutation analysis in 70 Dutch families with Usher syndrome type II.	Pennings RJ	Human mutation	2004	PMID: 15241801
Evaluation of visual impairment in Usher syndrome 1b and Usher syndrome 2a.	Pennings RJ	Acta ophthalmologica Scandinavica	2004	PMID: 15043528
Identification of 51 novel exons of the Usher syndrome type 2A (USH2A) gene that encode multiple conserved functional domains and that are mutated in patients with Usher syndrome type II.	van Wijk E	American journal of human genetics	2004	PMID: 15015129
Genomic structure and identification of novel mutations in usherin, the gene responsible for Usher syndrome type IIa.	Weston MD	American journal of human genetics	2000	PMID: 10729113
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-
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Text-mined citations for rs121912600 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jul 27, 2026