chr1-215798944-A-C

Position:

chr1-215798944-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The variant NM_206933.4:c.9921T>G in USH2A is a missense variant predicted to cause substitution of cysteine by tryptophan at amino acid 3307 (p.Cys3307Trp). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.585, which meets no codes. The variant has been reported in three compound heterozygous probands, two who were diagnosed with retinitis pigmentosa, and all with a likely pathogenic/pathogenic second USH2A variant in phase unknown (PM3; PMIDs: 32531858, 34906470, 36819107). In summary, this variant meets the criteria to be classified as uncertain significance for AR Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16044155/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel P:4U:6

Conservation

PhyloP100: 0.139

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.9921T>G	p.Cys3307Trp	missense_variant	50/72	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.9921T>G	p.Cys3307Trp	missense_variant	50/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.9921T>G	p.Cys3307Trp	missense_variant	50/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD4 exome

AF:

0.0000198

AC:

AN:

1461756

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000252

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:4Uncertain:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 3307 of the USH2A protein (p.Cys3307Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 26667666, 32531858; 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: 226441). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on USH2A protein function. This variant disrupts the p.Cys3307Tyr amino acid residue in USH2A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28559085; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 01, 2021	- -

Usher syndrome type 1

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

GeneReviews

May 19, 2016

- -

USH2A-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 22, 2024

The USH2A c.9921T>G variant is predicted to result in the amino acid substitution p.Cys3307Trp. This variant has been reported along with a second USH2A variant in multiple individuals with Usher syndrome or retinal disease (Bonnet et al. 2011. PubMed ID: 21569298; Ge et al. 2015. PubMed ID: 26667666; Table S1, Weisschuh et al. 2020. PubMed ID: 32531858; Table S4, Panneman et al. 2023. PubMed ID: 36819107). An alternate substitution of this amino acid residue (p.Cys3307Tyr) has also been reported in individuals with Usher syndrome or retinal disease (Table S1, Stone et al. 2017. PubMed ID: 28559085). This variant has not been reported in a large population database, indicating this variant is rare. Given the evidence, we interpret this variant as likely pathogenic. -

Usher syndrome

Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Feb 21, 2024

The variant NM_206933.4:c.9921T>G in USH2A is a missense variant predicted to cause substitution of cysteine by tryptophan at amino acid 3307 (p.Cys3307Trp). The variant is absent from gnomAD v2.1.1 (PM2_Supporting). The REVEL computational prediction analysis tool produced a score of 0.585, which meets no codes. The variant has been reported in three compound heterozygous probands, two who were diagnosed with retinitis pigmentosa, and all with a likely pathogenic/pathogenic second USH2A variant in phase unknown (PM3; PMIDs: 32531858, 34906470, 36819107). In summary, this variant meets the criteria to be classified as uncertain significance for AR Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM2_Supporting, PM3. (ClinGen Hearing Loss VCEP specifications version 2; 2/21/2024). -

Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Ocular Genomics Institute, Massachusetts Eye and Ear

Apr 08, 2021

The USH2A c.9921T>G 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. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Usher syndrome type 2A

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 10, 2020

- -

Retinitis pigmentosa

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

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

Apr 01, 2021

The p.Cys3307Trp 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. Based on this evidence we have classified this variant as a Variant of Uncertain Significance. If you have any questions about the classification please reach out to the Pierce Lab. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Benign

-0.093

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.78

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.97

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-8.3

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MVP

0.82

MPC

0.26

ClinPred

1.0

GERP RS

-4.1

Varity_R

0.94

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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