VCV000166434.60 - ClinVar

NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

Germline

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.

(21)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(10); Likely pathogenic(3); Uncertain significance(3)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

Variation ID: 166434 Accession: VCV000166434.60

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1q41 1: 215675336 (GRCh38) [ NCBI UCSC ] 1: 215848678 (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	Jan 30, 2015	Oct 20, 2024	Feb 15, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_206933.4:c.12575G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_996816.3:p.Arg4192His	missense
NM_206933.3:c.12575G>A
NC_000001.11:g.215675336C>T
NC_000001.10:g.215848678C>T
NG_009497.2:g.753113G>A
	O75445:p.Arg4192His

... more HGVS ... less HGVS

Protein change

R4192H

Other names

Canonical SPDI

NC_000001.11:215675335:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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.

0.00020 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00031

Trans-Omics for Precision Medicine (TOPMed) 0.00035

The Genome Aggregation Database (gnomAD) 0.00046

Exome Aggregation Consortium (ExAC) 0.00047

The Genome Aggregation Database (gnomAD), exomes 0.00059

Links

ClinGen: CA179511 UniProtKB: O75445#VAR_068358 dbSNP: rs199605265 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		-	-	GRCh38 GRCh37	7084	8579

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.
not specified	Uncertain significance (1)	criteria provided, single submitter	Jul 16, 2014	RCV000152569.6
Usher syndrome type 2A	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Feb 1, 2024	RCV001004143.7
not provided	Conflicting interpretations of pathogenicity (6)	criteria provided, conflicting classifications	Feb 15, 2024	RCV000480057.46
Retinitis pigmentosa	Pathogenic (4)	criteria provided, single submitter	Apr 1, 2021	RCV000505125.7
Usher syndrome	Pathogenic (1)	criteria provided, single submitter	Mar 23, 2023	RCV003226215.3
Retinitis pigmentosa 39	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 8, 2021	RCV000675140.6
USH2A-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 2, 2023	RCV004532711.1
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Aug 16, 2019	RCV001074420.4

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.	More information 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 (May 07, 2015)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331629.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018	Publications: PubMed (7) PubMed: 20507924‚ 21151602‚ 22135276‚ 22334370‚ 23591405‚ 23991284‚ 25649381 Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A http://www.lovd.nl/USH2A http://www.lovd.nl/USH2A Number of individuals with the variant: 3 Sex: mixed
Pathogenic (Feb 08, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 39 Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001520107.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A Affected status: yes Allele origin: unknown	3billion Accession: SCV004013681.1 First in ClinVar: Jul 22, 2023 Last updated: Jul 22, 2023	Publications: PubMed (1) PubMed: 23940504 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.057%). Protein truncation variants are a common disease-causing … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.057%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000166434 / 3billion dataset). A different missense change at the same codon (p.Arg4192Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000281818 / PMID: 23940504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Number of individuals with the variant: 4 Clinical Features: Rod-cone dystrophy (present) , Bull's eye maculopathy (present) , Hearing impairment (present)
Pathogenic (Aug 02, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	USH2A-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004119222.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The USH2A c.12575G>A variant is predicted to result in the amino acid substitution p.Arg4192His. This variant has been reported in the compound heterozygous state as … (more) The USH2A c.12575G>A variant is predicted to result in the amino acid substitution p.Arg4192His. This variant has been reported in the compound heterozygous state as causative for retinitis pigmentosa (RP) and Usher syndrome type 2 (Lenassi et al. 2015. PubMed ID: 25649381; Neveling et al. 2012. PubMed ID: 22334370; Avila-Fernandez et al. 2010. PubMed ID: 21151602). At PreventionGenetics, we have seen this variant either in the homozygous state or along with a second causative variant in several unrelated patients (internal data). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215848678-C-T), which is relatively common for disease causing variant. The majority of submitters to ClinVar interpret this variant as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166434/). Given the evidence, we interpret c.12575G>A (p.Arg4192His) as pathogenic. (less)
Uncertain significance (Jul 16, 2014)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	Not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000201820.3 First in ClinVar: Jan 30, 2015 Last updated: Jan 30, 2015	Publications: PubMed (3) PubMed: 20507924‚ 21151602‚ 23991284 Comment: The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these … (more) The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these individuals were homozygous or compound heterozygous, and one was only reported to be heterozygous for this variant but there was no information about a second variant. The Arg4192His variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199605265). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 4192 is not conserved in mammals or evolutionary distant species, including many species carrying a histidine (His) at this position, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the Arg4192His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Arg4192His variant is uncertain, these data suggest that is more likely to be benign. (less) Number of individuals with the variant: 1
Pathogenic (Aug 16, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001240002.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely pathogenic (Oct 23, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001447609.1 First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Mar 23, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Usher syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV003922470.1 First in ClinVar: May 13, 2023 Last updated: May 13, 2023	Publications: PubMed (5) PubMed: 32531858‚ 30902645‚ 35672425‚ 21151602‚ 29276052 Comment: Variant summary: USH2A c.12575G>A (p.Arg4192His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. … (more) Variant summary: USH2A c.12575G>A (p.Arg4192His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 280866 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00057 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa or hereditary retinal disorders (Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022) and this variant co-segregated with the disease (Avila-Fernandez_2010, Martin-Merida_2019). 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. 15 submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely pathogenic (n=2) and pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Uncertain significance (Jun 18, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003828074.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001057184.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024	Publications: PubMed (8) PubMed: 21151602‚ 22135276‚ 22334370‚ 23991284‚ 25649381‚ 28118666‚ 28559085‚ 28894305 Comment: This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4192 of the USH2A protein (p.Arg4192His). … (more) This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4192 of the USH2A protein (p.Arg4192His). This variant is present in population databases (rs199605265, gnomAD 0.9%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild or late onset deafness and/or nonsyndromic retinal disease (PMID: 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166434). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
Likely pathogenic (Jun 22, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Usher syndrome type 2A (Autosomal recessive inheritance) Affected status: yes Allele origin: paternal	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV004812146.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Comment: Criteria applied: PM3_VSTR,PM5,BP4 Clinical Features: Cone-rod dystrophy (present) Sex: male
Pathogenic (Feb 15, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565653.8 First in ClinVar: Apr 27, 2017 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, … (more) In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, 23591405, 26427457, 28131284, 26880948, 28559085, 21151602, 22334370, 27596865, 28118666, 30217765, 32326409, 31980526, 32036094, 32581362, 26806561, 25412400, 28041643, 26927203, 29276052, 31049658, 31736247, 32269941, 31456290, 28805479, 27160483, 20507924, 22135276, 34327195, 32675063, 28894305, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249) (less)
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 39 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573312.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (13) PubMed: 28041643‚ 27596865‚ 26927203‚ 26806561‚ 25649381‚ 23591405‚ 23991284‚ 22334370‚ 22135276‚ 21151602‚ 20507924‚ 28559085‚ 27160483 Comment: The USH2A c.12575G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The USH2A c.12575G>A 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: PS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Apr 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Retinitis pigmentosa (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001950420.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021	Publications: PubMed (14) PubMed: 34906470‚ 28041643‚ 27596865‚ 26927203‚ 26806561‚ 25649381‚ 23591405‚ 22334370‚ 22135276‚ 21151602‚ 20507924‚ 28559085‚ 27160483‚ 23991284 Comment: The p.Arg4192His variant in USH2A was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics … (more) The p.Arg4192His 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. (less)
Likely pathogenic (Feb 01, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Usher syndrome type 2A Affected status: no Allele origin: germline	Laboratory of Medical Genetics, National & Kapodistrian University of Athens Accession: SCV005051994.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024
Uncertain significance (Jul 01, 2019)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246243.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 2
Likely pathogenic (Jan 01, 2015)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	NIHR Bioresource Rare Diseases, University of Cambridge Accession: SCV000598777.1 First in ClinVar: Sep 09, 2017 Last updated: Sep 09, 2017	Publications: PubMed (2) PubMed: 28041643‚ 21151602 Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: European
Uncertain significance (Apr 01, 2018)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: unknown	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet Study: VeluxRD Accession: SCV000926717.2 First in ClinVar: Jul 21, 2019 Last updated: Sep 03, 2023	Publications: PubMed (1) PubMed: 30718709
Uncertain significance (Jan 26, 2022)	no assertion criteria provided Method: clinical testing	Usher syndrome type 2A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV001162876.2 First in ClinVar: Feb 29, 2020 Last updated: Oct 15, 2022	Publications: PubMed (5) PubMed: 21151602‚ 25649381‚ 20507924‚ 28559085‚ 27596865
Uncertain significance (May 07, 2019)	no assertion criteria provided Method: clinical testing	Retinitis pigmentosa 39 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000800729.2 First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019	Publications: PubMed (16) PubMed: 27208204‚ 30543658‚ 27160483‚ 26806561‚ 25412400‚ 22135276‚ 25649381‚ 27596865‚ 28157192‚ 21151602‚ 28894305‚ 23991284‚ 20507924‚ 22334370‚ 26927203‚ 23591405
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161337.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
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Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.057%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.66). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000166434 / 3billion dataset). A different missense change at the same codon (p.Arg4192Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000281818 / PMID: 23940504). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Comment:

The USH2A c.12575G>A variant is predicted to result in the amino acid substitution p.Arg4192His. This variant has been reported in the compound heterozygous state as causative for retinitis pigmentosa (RP) and Usher syndrome type 2 (Lenassi et al. 2015. PubMed ID: 25649381; Neveling et al. 2012. PubMed ID: 22334370; Avila-Fernandez et al. 2010. PubMed ID: 21151602). At PreventionGenetics, we have seen this variant either in the homozygous state or along with a second causative variant in several unrelated patients (internal data). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215848678-C-T), which is relatively common for disease causing variant. The majority of submitters to ClinVar interpret this variant as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166434/). Given the evidence, we interpret c.12575G>A (p.Arg4192His) as pathogenic.

Comment:

The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these individuals were homozygous or compound heterozygous, and one was only reported to be heterozygous for this variant but there was no information about a second variant. The Arg4192His variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199605265). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 4192 is not conserved in mammals or evolutionary distant species, including many species carrying a histidine (His) at this position, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the Arg4192His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Arg4192His variant is uncertain, these data suggest that is more likely to be benign.

Comment:

Variant summary: USH2A c.12575G>A (p.Arg4192His) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 280866 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00057 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa or hereditary retinal disorders (Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022) and this variant co-segregated with the disease (Avila-Fernandez_2010, Martin-Merida_2019). 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. 15 submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely pathogenic (n=2) and pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4192 of the USH2A protein (p.Arg4192His). This variant is present in population databases (rs199605265, gnomAD 0.9%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild or late onset deafness and/or nonsyndromic retinal disease (PMID: 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 166434). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, 23591405, 26427457, 28131284, 26880948, 28559085, 21151602, 22334370, 27596865, 28118666, 30217765, 32326409, 31980526, 32036094, 32581362, 26806561, 25412400, 28041643, 26927203, 29276052, 31049658, 31736247, 32269941, 31456290, 28805479, 27160483, 20507924, 22135276, 34327195, 32675063, 28894305, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249)

Comment:

The USH2A c.12575G>A 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: PS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic.

Comment:

The p.Arg4192His 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, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Clinical exome sequencing for inherited retinal degenerations at a tertiary care center.	Ganapathi M	Scientific reports	2022	PMID: 35672425
The importance of automation in genetic diagnosis: Lessons from analyzing an inherited retinal degeneration cohort with the Mendelian Analysis Toolkit (MATK).	Zampaglione E	Genetics in medicine : official journal of the American College of Medical Genetics	2022	PMID: 34906470
Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period.	Weisschuh N	Human mutation	2020	PMID: 32531858
Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases.	Martin-Merida I	Ophthalmology	2019	PMID: 30902645
Molecular genetic analysis using targeted NGS analysis of 677 individuals with retinal dystrophy.	Jespersgaard C	Scientific reports	2019	PMID: 30718709
Next-generation sequencing identifies unexpected genotype-phenotype correlations in patients with retinitis pigmentosa.	Birtel J	PloS one	2018	PMID: 30543658
Nonsyndromic Retinitis Pigmentosa in the Ashkenazi Jewish Population: Genetic and Clinical Aspects.	Kimchi A	Ophthalmology	2018	PMID: 29276052
Electroretinography Reveals Difference in Cone Function between Syndromic and Nonsyndromic USH2A Patients.	Sengillo JD	Scientific reports	2017	PMID: 28894305
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Unravelling the genetic basis of simplex Retinitis Pigmentosa cases.	Bravo-Gil N	Scientific reports	2017	PMID: 28157192
Genome-Wide Detection of Copy Number Variations in Unsolved Inherited Retinal Disease.	Huang XF	Investigative ophthalmology & visual science	2017	PMID: 28118666
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
Advanced diagnostic genetic testing in inherited retinal disease: experience from a single tertiary referral centre in the UK National Health Service.	Khan KN	Clinical genetics	2017	PMID: 27160483
Next-generation sequencing-based molecular diagnosis of 35 Hispanic retinitis pigmentosa probands.	Zhang Q	Scientific reports	2016	PMID: 27596865
Molecular findings from 537 individuals with inherited retinal disease.	Ellingford JM	Journal of medical genetics	2016	PMID: 27208204
Visual Prognosis in USH2A-Associated Retinitis Pigmentosa Is Worse for Patients with Usher Syndrome Type IIa Than for Those with Nonsyndromic Retinitis Pigmentosa.	Pierrache LH	Ophthalmology	2016	PMID: 26927203
Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa.	Perez-Carro R	Scientific reports	2016	PMID: 26806561
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
Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.	Consugar MB	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25412400
Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies.	Glöckle N	European journal of human genetics : EJHG	2014	PMID: 23591405
Patient-specific iPSC-derived photoreceptor precursor cells as a means to investigate retinitis pigmentosa.	Tucker BA	eLife	2013	PMID: 23991284
Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis.	Corton M	PloS one	2013	PMID: 23940504
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
Mutation analysis of 272 Spanish families affected by autosomal recessive retinitis pigmentosa using a genotyping microarray.	Ávila-Fernández A	Molecular vision	2010	PMID: 21151602
Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.	McGee TL	Journal of medical genetics	2010	PMID: 20507924
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A	-	-	-	-
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Text-mined citations for rs199605265 ...

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 Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

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Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs199605265 ...