rs750396156

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 3 ACMG points: 3P and 0B. PP4PM3

This summary comes from the ClinGen Evidence Repository: The c.12574C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 4192 (p.Arg4192Cys). The highest population minor allele frequency in gnomAD v4.0 is 0.012% (144/1180032 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.599, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant was observed in at least 2 individuals with Usher syndrome and at least 10 individuals with isolated retinitis pigmentosa (RP) who were either homozygous or who carried a second P/LP variant in USH2A (PMID:24516651, 27460420, 23940504, 27157150, 34906470, 24625443, 28127548, 28041643, 30190494, 29912909, 32176120, 33576794, 34781295, 36785559). At least one of these individuals was clinically evaluated and confirmed to have both sensorineural hearing loss and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID:27460420). Of note, an additional proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (PMID:29912909), however the VCEP felt that the evidence supporting the pathogenicity of the p.Arg4192Cys variant outweighed this observation. Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2, 11.15.2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA1393449/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:22U:1

Conservation

PhyloP100: 3.10

Publications

23 publications found

Variant links:

Genes affected

USH2A (HGNC:12601): (usherin) This gene encodes a protein that contains laminin EGF motifs, a pentaxin domain, and many fibronectin type III motifs. The protein is found in the basement membrane, and may be important in development and homeostasis of the inner ear and retina. Mutations within this gene have been associated with Usher syndrome type IIa and retinitis pigmentosa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2008]

USH2A Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 3 ACMG points.

PM3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12574C>T	p.Arg4192Cys	missense_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.12574C>T	p.Arg4192Cys	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.12574C>T	p.Arg4192Cys	missense_variant	Exon 63 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249476

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000713

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000985

AC:

144

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000127

AC:

141

AN:

1112002

Other (OTH)

AF:

0.0000497

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.585

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000915

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:22Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: PM3:Very Strong, PM2, PM5 -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 10, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: 32531858, 34758253, 23940504, 24516651, 27157150, 24625443, 25649381, 28041643, 32176120, 32581362, 34426522, 33576794, 36011334, 34948090, 32637036, 34781295, 30190494, 28127548, 35266249, 36785559, 29912909, 27460420) -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4192 of the USH2A protein (p.Arg4192Cys). This variant is present in population databases (rs750396156, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (arRP) (PMID: 23940504, 27157150, 29912909, 32176120, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 281818). 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 80%. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39

Pathogenic:4

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2016

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 22, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A c.12574C>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: PM2, PM3, PP1, PP4, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. -

Retinitis pigmentosa

Pathogenic:4

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2021

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg4192Cys 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: PM2, PM3, PP1, PP4, BP2. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Oct 01, 2024

Lab De Baere, Eye and Developmental Genetics Lab, Ghent University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG/AMP guidelines: PM2, PP4_PP, PP1, PM3_2 -

Usher syndrome

Pathogenic:3

Dec 31, 2022

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

May 19, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH2A c.12574C>T (p.Arg4192Cys) results in a non-conservative amino acid change located in the fibronectin type III domain (IPR003961) 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 3.2e-05 in 249476 control chromosomes (gnomAD). c.12574C>T has been reported in the literature as a biallelic genotype in at least two individuals affected with Usher Syndrome and multiple individuals affected with retinitis pigmentosa, including at least one family where it segregated with disease (e.g.Corton_2013, Coppieters_2014, de Castro-Miro_2014, Bonnet_2016) . 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. However, another variant affecting the same amino acid (p.R4192H) has also been classified as pathogenic by our laboratory, suggesting Arg4192 may be important for protein function. The following publications have been ascertained in the context of this evaluation (PMID: 27460420, 24625443, 23940504, 24516651). Thirteen submitters, including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=5)/likely pathogenic (n=6) or VUS (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 15, 2023

ClinGen Hearing Loss Variant Curation Expert Panel

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

The c.12574C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 4192 (p.Arg4192Cys). The highest population minor allele frequency in gnomAD v4.0 is 0.012% (144/1180032 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.599, which is neither above nor below the thresholds predicting a damaging or benign impact on USH2A function. This variant was observed in at least 2 individuals with Usher syndrome and at least 10 individuals with isolated retinitis pigmentosa (RP) who were either homozygous or who carried a second P/LP variant in USH2A (PMID: 24516651, 27460420, 23940504, 27157150, 34906470, 24625443, 28127548, 28041643, 30190494, 29912909, 32176120, 33576794, 34781295, 36785559). At least one of these individuals was clinically evaluated and confirmed to have both sensorineural hearing loss and retinitis pigmentosa, which are highly specific for Usher syndrome (PP4; PMID: 27460420). Of note, an additional proband harbored this variant in cis with the known pathogenic p.Cys759Phe variant (PMID: 29912909), however the VCEP felt that the evidence supporting the pathogenicity of the p.Arg4192Cys variant outweighed this observation. Patients with this variant may present with either autosomal recessive (AR) Usher syndrome or with AR isolated RP. Isolated RP presentations are more common when the variant is seen with missense variants while Usher syndrome is more common when it is found with truncating variants. In summary, the clinical significance of this variant is likely pathogenic based on the ACMG/AMP criteria applied as specified by the Hearing Loss Expert Panel: PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2, 11.15.2023) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:2

Feb 15, 2017

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:2

Jan 17, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome type 2A

Pathogenic:1

Oct 09, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (RP; MIM# 6138093). Null variants are associated with Usher syndrome while homozygous missense which lead to partially functional proteins typically causes non-syndromic RP (PMID: 20301515). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v4: 149 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v4: 500 heterozygotes, 1 homozygote). (I) 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. This variant has been classified as likely pathogenic by an expert panel (ClinVar). Specifically, it has been observed compound heterozygous with c.11874_11875delCA in a 17 year old individual with night blindness, mild peripheral field constriction, and hearing impairment (PMID: 36011334). In addition, it has been observed in compound heterozygous with p.(Cys795Phe) in an 18 year old individual diagnosed with simplex retinitis pigmentosa (PMID: 30190494). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.43

MutationAssessor

Pathogenic

3.0

PhyloP100

3.1

PrimateAI

Benign

0.23

PROVEAN

Uncertain

-4.0

REVEL

Uncertain

0.60

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.76

MutPred

0.69

Loss of MoRF binding (P = 0.0091);

MVP

0.97

MPC

0.25

ClinPred

0.90

GERP RS

5.3

Varity_R

0.36

gMVP

0.80

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over