rs201527662

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong

The NM_206933.4(USH2A):c.2802T>G(p.Cys934Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000905 in 1,614,032 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000087 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:20U:3

Conservation

PhyloP100: 1.35

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 12 ACMG points.

PM1

In a disulfide_bond (size 14) in uniprot entity USH2A_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-216246592-A-C is Pathogenic according to our data. Variant chr1-216246592-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 143179.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216246592-A-C is described in Lovd as [Likely_pathogenic]. Variant chr1-216246592-A-C is described in Lovd as [Pathogenic]. Variant chr1-216246592-A-C is described in Lovd as [Pathogenic]. Variant chr1-216246592-A-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.2802T>G	p.Cys934Trp	missense_variant	13/72	ENST00000307340.8	NP_996816.3
USH2A	NM_007123.6 linkuse as main transcript	c.2802T>G	p.Cys934Trp	missense_variant	13/21		NP_009054.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.2802T>G	p.Cys934Trp	missense_variant	13/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.2802T>G	p.Cys934Trp	missense_variant	13/21	1		ENSP00000355909		O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.2802T>G	p.Cys934Trp	missense_variant	13/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00327

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000211

AC:

AN:

251078

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00250

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000869

AC:

127

AN:

1461736

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000383

Gnomad4 EAS exome

AF:

0.00244

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000125

AC:

AN:

152296

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00347

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000237

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.000214

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:20Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Usher syndrome type 2A

Pathogenic:7Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000143179, PMID:21686329, PS1_S).It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000202, PM2_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.849, PP3_P). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 retinitis pigmentosa 39 (MIM#6138093) and type 2A Usher syndrome (MIM#276901). (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 tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 57 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2: 2 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated laminin EGF domain (Decipher). (I) 0801 - This variant has strong previous evidence of pathogenicity in multiple unrelated individuals with retinitis pigmentosa and Usher syndrome (ClinVar, PMID: 32893482). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.C934W in USH2A (NM_206933.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.C934W variant is observed in 46/18,376 (0.2503%) alleles from individuals of East Asian background in gnomAD Exomes and in 4/1,008 (0.3968%) alleles from individuals of East Asian background in 1000 Genomes. This variant was found in ClinVar (Variant 143179) with a classification of Conflicting Interpretations Of Pathogenicity and a review status of (1 star) criteria provided, conflicting interpretations. There is a large physicochemical difference between cysteine and tryptophan, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. For these reasons, this variant has been classified as Uncertain Significance. A different heterozygous variant in the USH2A gene has been detected in the spouse -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 20, 2019	NM_206933.2(USH2A):c.2802T>G(C934W) is classified as likely pathogenic in the context of USH2A-related disorders. Sources cited for classification include the following: PMID 24938718, 25324289, 26310143, 27460420 and 26338283. Classification of NM_206933.2(USH2A):c.2802T>G(C934W) 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	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

Retinitis pigmentosa 39

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 17, 2023	- -
Pathogenic, criteria provided, single submitter	research	Pangenia Genomics, Pangenia Inc.	Nov 18, 2021	The USH2A, c.2802T>G (p.Cys934Trp) variant is at extremely low frequency in population database; allele frequency in East Asia population is 0. 0025 by gnomAD v2.1.1. This variant is detected in trans with a pathogenic variant [USH2A, c.9570+1G>A] . This variant has been previously reported to be detected in numerous patients affected by retinitis pigmentosa or Usher syndrome as homozygote [PMID: 26338283], or in combination with another null variant in USH2A gene [PMID: 24938718, 25649381, 30948794, 33105608, 26338283], including frameshift and canonical splice sites variants (c.8368delT, c.8730dupT, c.9570+1G>A, c.99_100insT, c.5858-1G>A, c.5158delC, c.11811_11812delCT, c.12409delA, c.710delT). In at least 3 patients, the other null variant was confirmed to be in trans with this variant [PMID: 24938718, 30948794]. Multiple lines of computational evidence support a deleterious effect on the gene or gene product, REVEL = 0.849. This variant has been reported to co-segregate with retinitis pigmentosa or Usher syndrome in several families [PMID: 24938718, 26310143, 21686329].There are multiple submissions of this variant in ClinVar (Variation ID: 143179). -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 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: 26992781, 29899460, 34416374, 33629268, 32531858, 31904091, 31045651, 31054281, 25262649, 25356976, 25474345, 26310143, 21686329, 24938718, 25324289, 27460420, 25649381, 25078356, 26338283, 28041643, 28704127, 29625443, 30487145, 29074561, 32100970, 31960602, 31213501, 32188678, 31872526, 30948794, 31456290, 32203226, 30896630, 32581362, 32893482, 33090715, 33105608, 34426522, 33124170, 32675063, 33608557, 31964843, 36464167, 36110214, 37981655, 33749171, 33781268, 33946315, 33691693, 32037395, 35314707, 34721897, 35266249, 35052368, 36597107, 36729443, 36819107) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 934 of the USH2A protein (p.Cys934Trp). This variant is present in population databases (rs201527662, gnomAD 0.2%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 25356976, 26338283, 27160483, 27460420, 29625443, 29899460, 30948794). 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: 143179). 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)	Jan 19, 2017	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jul 16, 2019	- -
Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Pathogenic, no assertion criteria provided	literature only	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -
Uncertain significance, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -

Usher syndrome type 2

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Sharon lab, Hadassah-Hebrew University Medical Center

Jun 23, 2019

- -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Nov 21, 2022

Variant summary: USH2A c.2802T>G (p.Cys934Trp) results in a non-conservative amino acid change located in the Laminin-type EGF domain (IPR002049) 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 0.00021 in 251078 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00021 vs 0.011), allowing no conclusion about variant significance. c.2802T>G has been reported in the literature as a biallelic genotype in multiple individuals affected with retinitis pigmentosa and Usher syndrome (e.g. Oishi_2014, Zheng_2015, Koyanagi_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. Fifteen ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, five classified the variant as likely pathogenic, and seven classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.77

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.3

H;H

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-9.1

D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.96

MVP

0.93

MPC

0.26

ClinPred

0.99

GERP RS

3.7

Varity_R

0.99

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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