rs148660051

Positions:

chr1-215790168-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_206933.4(USH2A):c.10073G>A(p.Cys3358Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,914 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 3 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:28

Conservation

PhyloP100: 7.38

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 Pathogenic. Variant got 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.86

PP5

Variant 1-215790168-C-T is Pathogenic according to our data. Variant chr1-215790168-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 197932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215790168-C-T is described in Lovd as [Likely_pathogenic]. Variant chr1-215790168-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.10073G>A	p.Cys3358Tyr	missense_variant	51/72	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.10073G>A	p.Cys3358Tyr	missense_variant	51/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.10073G>A	p.Cys3358Tyr	missense_variant	51/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000346

AC:

AN:

251094

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000688

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.00105

AC:

1537

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000987

AC XY:

718

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.00134

Gnomad4 OTH exome

AF:

0.000679

GnomAD4 genome

AF:

0.000513

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000511

AC XY:

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000808

Hom.:

Bravo

AF:

0.000499

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000288

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000533

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:28

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 39

Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Sep 27, 2021	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Retinitis pigmentosa 39, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PM3-Strong => PM3 upgraded in strength to Strong (PMID:22334370) (PMID:25649381). -
Likely pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.10073G>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, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Dec 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 29, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A

Pathogenic:7

Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, University Hospital Schleswig-Holstein	Aug 25, 2021	- -
Likely pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 19, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 17, 2019	NM_206933.2(USH2A):c.10073G>A(C3358Y) is classified as likely pathogenic in the context of USH2A-related disorders and is primarily associated with retinitis pigmentosa. Sources cited for classification include the following: PMID 22004887, 22334370, 26667666, 25472526, 25097241, 25649381 and 20507924. Classification of NM_206933.2(USH2A):c.10073G>A(C3358Y) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (MIM# 6138093). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from cysteine to tyrosine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 111 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in at least ten individuals with both Usher syndrome, type 2A (MIM#276901) and retinitis pigmentosa (MIM# 6138093), and classified as both like pathogenic and pathogenic by diagnostic laboratories in Clinvar (PMID: 22004887, 25649381). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 30, 2019	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing by following sources [PMID: 25097241, 20507924, 25472526, 22004887, ClinVar ID: 197932] -
Likely pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Jan 27, 2016	The c.10073G>A (p.Cys3358Tyr) missense variant in the USH2A gene has been previously reported in several individuals affected with Usher Syndrome or Retinitis Pigmentosa. This allele was observed in 13 cases out of 914 affected alleles (Lenassi et al., 2015) and is significantly higher than the allele frequency in the ExAC database (13/121292). This variant is often seen in trans with other pathogenic variants (Garcia-Garcia et al., 2011; Le Quesne Stabej et al., 2012; Neveling et al., 2012; Lenassi et al., 2015). This c.10073G>A allele has been reported at low frequency, or is absent in other population databases (Exome Sequencing Project [ESP] = 0.058%, 1000 Genomes = NA). Multiple in silico algorithms predict this variant to have a deleterious effect GERP = 5.76; CADD = 22.4; PolyPhen = 1; SIFT = 0). Reputable diagnostic laboratories have reported this variant as either Likely Pathogenic or Pathogenic for either, Retinitis Pigmentosa or Usher Syndrome, Type 2A. Therefore, this collective evidence supports the classification of the c.10073G>A (p.Cys3358Tyr) as a recessive Likely Pathogenic variant for Usher syndrome, type IIA. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 3358 of the USH2A protein (p.Cys3358Tyr). This variant is present in population databases (rs148660051, gnomAD 0.07%). This missense change has been observed in individual(s) with Usher syndrome or retinal disease (PMID: 22004887, 22135276, 25472526, 28559085). 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: 197932). 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 95%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2023	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: 28559085, 32531858, 34758253, 22334370, 25472526, 22004887, 20507924, 25649381, 22135276, 21151602, 25999674, 25097241, 26667666, 29953849, 31456290, 31980526, 32176120, 32581362, 31589614, 33576794, 33258288, 33737949, 32037395, 35266249) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2018	- -

Retinitis pigmentosa

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	Jul 24, 2023	Clinical significance based on ACMG v2.0 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2021	The p.Cys3358Tyr variant in USH2A has been reported in over 15 individuals with retinitis pigmentosa, with at least 9 of these individuals being compound heterozygous for a pathogenic variant on the remaining copy of USH2A (Calzetti 2018 PMID:29953849, Garcia-Garcia 2011 PMID:22004887, LeQuesne Stabej 2012 PMID:22135276, Lenassi 2015 PMID:25649381, McGee 2010 PMID:20507924, Neveling 2012 PMID:22334370, Stone 2018 PMID:28559085, van Huet 2015 PMID:25999674, Wang 2014 PMID:25097241, Zhao 2015 PMID:25472526, Avila-Fernandez 2010 PMID:21151602). Two of these individuals were reported to have features of atypical type 2 Usher syndrome, with a later onset hearing loss (Garcia-Garcia 2011 PMID:22004887, Lenassi 2015 PMID:25649381), and one was reported to have hearing loss though age of onset was not noted (Calzetti 2018 PMID:29953849). The variant has been identified in 98/128872 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analysis suggest an impact to the protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa and/or atypical type 2 Usher syndrome, based on the previously reported individuals. ACMG/AMP criteria applied: PM3_VeryStrong, PM2_Supporting, PP3. -
Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Likely pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Likely pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	The p.Cys3358Tyr 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, PP3. 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. -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

May 11, 2022

Variant summary: USH2A c.10073G>A (p.Cys3358Tyr) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR003961) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 251094 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00035 vs 0.011), allowing no conclusion about variant significance. c.10073G>A has been reported in the literature in multiple individuals affected with Usher Syndrome/Retinitis Pigmentosa/Inherited Retinal Diseases (IRD) (example, Garcia-Garcia_2011, LeQuesneStabej_2012, Lenassi_2015, Neveling_2012, Wang_2014, Calzetti_2018, McGee_2010, Weisschuh_2020). 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. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 10, 2022

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Aug 15, 2019

- -

USH2A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2024

The USH2A c.10073G>A variant is predicted to result in the amino acid substitution p.Cys3358Tyr. This variant has been reported along with a second pathogenic variant in many individuals with autosomal recessive nonsyndromic retinitis pigmentosa or Usher syndrome (Calzetti et al. 2018. PubMed ID: 29953849; Table S4, Colombo et al. 2021. PubMed ID: 33576794; Lynn et al. 2023. PubMed ID: 36672815; Molina-Ramírez et al. 2020. PubMed ID: 32176120; Table S4, Panneman et al. 2023. PubMed ID: 36819107), although it has been associated primarily with nonsyndromic retinal degeneration in patients without early onset hearing loss (Leanassi et al. 2015. PubMed ID: 25649381). This variant is reported in 0.076% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MVP

0.88

MPC

0.28

ClinPred

0.91

GERP RS

5.8

Varity_R

0.93

gMVP

0.94

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