rs750396156

Positions:

chr1-215675337-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 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:18U:1

Conservation

PhyloP100: 3.10

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.12574C>T	p.Arg4192Cys	missense_variant	63/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.12574C>T	p.Arg4192Cys	missense_variant	63/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.12574C>T	p.Arg4192Cys	missense_variant	63/73			ENSP00000501296		O75445-3

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

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

249476

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135004

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000127

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

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:18Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:6Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2015	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2024	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2024	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). 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 expected to disrupt USH2A protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	USH2A: PM3:Very Strong, PM2, PM5 -

Retinitis pigmentosa 39

Pathogenic:4

Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	Sep 01, 2016	- -

Usher syndrome

Pathogenic:3

Likely pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Nov 15, 2023	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) -
Likely pathogenic, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	Dec 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 19, 2023	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. -

Retinitis pigmentosa

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	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. -
Likely pathogenic, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Feb 15, 2017

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jan 17, 2019

- -

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

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

MutationTaster

Benign

0.99

D;D

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over