rs35818432

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4_StrongBS2_Supporting

The NM_206933.4(USH2A):c.1663C>G(p.Leu555Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000972 in 1,613,940 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00099 ( 2 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5B:10

Conservation

PhyloP100: 3.10

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 18 uncertain in NM_206933.4

BP4

Computational evidence support a benign effect (MetaRNN=0.035342634).

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.1663C>G	p.Leu555Val	missense_variant	Exon 10 of 72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 link	c.1663C>G	p.Leu555Val	missense_variant	Exon 10 of 21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
USH2A	ENST00000307340.8 link	c.1663C>G	p.Leu555Val	missense_variant	Exon 10 of 72	1	NM_206933.4	ENSP00000305941.3	O75445-1
USH2A	ENST00000366942.3 link	c.1663C>G	p.Leu555Val	missense_variant	Exon 10 of 21	1		ENSP00000355909.3	O75445-2
USH2A	ENST00000674083.1 link	c.1663C>G	p.Leu555Val	missense_variant	Exon 10 of 73			ENSP00000501296.1	O75445-3

Frequencies

GnomAD3 genomes

AF:

0.000841

AC:

128

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000785

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00129

AC:

323

AN:

251082

AF XY:

0.00150

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00179

Gnomad OTH exome

AF:

0.00229

GnomAD4 exome

AF:

0.000985

AC:

1440

AN:

1461640

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

792

AN XY:

727128

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33474

American (AMR)

AF:

0.00154

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00241

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39648

South Asian (SAS)

AF:

0.000789

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.000337

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00885

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000969

AC:

1077

AN:

1111884

Other (OTH)

AF:

0.00149

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

146

219

292

365

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000840

AC:

128

AN:

152300

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41580

American (AMR)

AF:

0.000784

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00137

AC:

AN:

68010

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00136

Hom.:

Bravo

AF:

0.000975

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00129

AC:

157

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00284

EpiControl

AF:

0.00290

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:6

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: BP4, BS2 -

Nov 17, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25262649, 22995991, 14676276, 22004887, 21228398, 11311042, 27884173, 21569298, 29068140, 30245029, 31456290, 32707200) -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Usher syndrome type 2A

Pathogenic:1Uncertain:2Benign:1

Jan 11, 2020

Natera, Inc.

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 18, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 24, 2014

Laboratory of Prof. Karen Avraham, Tel Aviv University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The c.1663C>G:p.(Leu555Val) variant, a founder in the jewish population, was reported as pathogenic in at least 3 papers (PMID:11311042; 12525556; 19683999). Our case is an additional hearing impaired individual with asymetric HL, thus, eventhough it was calssified 'Likely benign' by most ClinVar submissions, we conclude 'Pathogenic'. -

not specified

Benign:3

Feb 19, 2025

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: USH2A c.1663C>G (p.Leu555Val) results in a conservative amino acid change located in the Laminin-type EGF domain (IPR002049) 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 0.0013 in 251082 control chromosomes in the gnomAD database, including 2 homozygotes. Additionally, a further homozygous individual was observed in gnomAD v4 and this variant is approaching MPAF (0.01) in the Middle Eastern subpopulation (0.009, 55 alleles). However,this frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.0013 vs 0.011), allowing no conclusion about variant significance. c.1663C>G has been reported in the multiply compound heterozygous state in the literature in numerous individuals affected with Usher Syndrome who have alternate pathogenic alleles which explain disease (example, Jaijo_2010, Vozzi_2011, as well as further studies PMID: 25558175, 12525556). These co-occurrences indicate that this variant is not likely to be responsible for the USH2A-related conditions in these individuals. At least one publication reports experimental evidence evaluating an impact on protein function, indicating no pathogenic effect (example, Bhattacharya_2003). The following publications have been ascertained in the context of this evaluation (PMID: 29068140, 30245029, 14676276, 21569298, 34781295, 19683999, 36460718, 11311042, 25262649, 21738395). ClinVar contains an entry for this variant (Variation ID: 48472). Based on the evidence outlined above, the variant was classified as benign. -

May 02, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu555Val in exon 10 of USH2A: This variant is not expected to have clinical s ignificance because it has been identified 0.2% (24/10136) of Ashkenazi Jewish c hromosomes and in 0.2% (212/126366) of European chromosomes including 1 homozygo te by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs35818432). It has been reported in cis with another pathogenic variant in USH2A (Jaijo 2009, Vozzi 2011). A study has shown that the variant does not i mpact protein function (Bhattacharya 2004). -

May 10, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinitis pigmentosa

Pathogenic:1Uncertain:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Retinitis pigmentosa 39

Uncertain:1

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A c.1663C>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, PP3, BP2. Based on this evidence we have classified this variant as Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.085

MetaRNN

Benign

0.035

T;T

MetaSVM

Uncertain

0.024

MutationAssessor

Pathogenic

3.6

H;H

PhyloP100

3.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

N;N

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.58

MVP

0.88

MPC

0.24

ClinPred

0.13

GERP RS

4.8

Varity_R

0.88

gMVP

0.66

Mutation Taster

=56/44

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over