1-216250989-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PP3PP4PM5PM2_SupportingPM3_Strong

This summary comes from the ClinGen Evidence Repository: The c.2081G>A in USH2A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 694 (p.Cys694Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002% (2/113290) in the European (non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.92 (PP3). This variant has been detected in at least three probands with Usher syndrome whereby pathogenic or suspected-pathogenic variants were confirmed in trans in two individuals (2.5 PM3_Strong points; PMID:28041643, Invitae Internal Data (SCV001372551.2)). Of the confirmed phase counts, the first harbored the p.Glu767SerfsTer21 variant and second harbored the p.Thr4425Met variant in USH2A (PMID:28041643, Invitae Internal Data). The third individual harbored the p.Cys3267Arg variant but phasing was not confirmed (Invitae Internal Data). At least one proband displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID:28041643). Two missense variants, c.2081G>C (p.Cys694Ser) and c.2080T>A (p.Cys694Ser), in the same codon have been classified as likely pathogenic or pathogenic for AR Usher syndrome by two submitters in ClinVar (PM5; ClinVar Variation ID:1217348, 813246). In summary, this variant meets the criteria to be classified as likely pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP4, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1396311/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

14
4
1

Clinical Significance

Likely pathogenic reviewed by expert panel P:7U:4

Conservation

PhyloP100: 7.16
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
PP3
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
USH2ANM_206933.4 linkc.2081G>A p.Cys694Tyr missense_variant Exon 12 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.2081G>A p.Cys694Tyr missense_variant Exon 12 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.2081G>A p.Cys694Tyr missense_variant Exon 12 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.2081G>A p.Cys694Tyr missense_variant Exon 12 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.2081G>A p.Cys694Tyr missense_variant Exon 12 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250854
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135552
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:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000212
AC:
31
AN:
1461764
Hom.:
0
Cov.:
32
AF XY:
0.0000193
AC XY:
14
AN XY:
727184
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:
0.0000261
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152162
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74304
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:7Uncertain:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Pathogenic:1Uncertain:4
-
Clinical Genetics, Academic Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jun 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 694 of the USH2A protein (p.Cys694Tyr). This variant is present in population databases (rs137954284, gnomAD 0.002%). This missense change has been observed in individual(s) with USH2A-related conditions (PMID: 20591486, 28041643; 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: 418533). 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. -

Oct 14, 2016
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); 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: 32581362, 20591486, 28041643) -

Usher syndrome Pathogenic:3
Jan 01, 2015
NIHR Bioresource Rare Diseases, University of Cambridge
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Oct 25, 2023
ClinGen Hearing Loss Variant Curation Expert Panel
Significance: Likely pathogenic
Review Status: reviewed by expert panel
Collection Method: curation

The c.2081G>A in USH2A is a missense variant predicted to cause substitution of cysteine to tyrosine at amino acid 694 (p.Cys694Tyr). The highest population minor allele frequency in gnomAD v2.1.1 is 0.002% (2/113290) in the European (non-Finnish) sub-population which is below the threshold defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.92 (PP3). This variant has been detected in at least three probands with Usher syndrome whereby pathogenic or suspected-pathogenic variants were confirmed in trans in two individuals (2.5 PM3_Strong points; PMID:28041643, Invitae Internal Data (SCV001372551.2)). Of the confirmed phase counts, the first harbored the p.Glu767SerfsTer21 variant and second harbored the p.Thr4425Met variant in USH2A (PMID:28041643, Invitae Internal Data). The third individual harbored the p.Cys3267Arg variant but phasing was not confirmed (Invitae Internal Data). At least one proband displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 28041643). Two missense variants, c.2081G>C (p.Cys694Ser) and c.2080T>A (p.Cys694Ser), in the same codon have been classified as likely pathogenic or pathogenic for AR Usher syndrome by two submitters in ClinVar (PM5; ClinVar Variation ID:1217348, 813246). In summary, this variant meets the criteria to be classified as likely pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Strong, PP4, PM5. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). -

Dec 31, 2022
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
May 31, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinitis pigmentosa 39 Pathogenic:1
Feb 08, 2024
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:1
Feb 20, 2019
Blueprint Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.50
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.52
D;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.86
D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.4
H;H
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-9.4
D;D
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.95
MVP
0.98
MPC
0.28
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.99
gMVP
0.99

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.

Other links and lift over

dbSNP: rs137954284; hg19: chr1-216424331; API