chr1-215728383-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 5 ACMG points: 5P and 0B. PM2_SupportingPM3PP3PP4

This summary comes from the ClinGen Evidence Repository: The c.11713C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3905 (p.Arg3905Cys). The highest population minor allele frequency in gnomAD v4 is 0.007% (6/75036) in the African / African American population, which meets the ClinGen Hearing Loss VCEP threshold (≤0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 6 individuals with Usher syndrome and at least 4 individuals with inherited retinal dystrophy. Of those individuals, 1 was homozygous and 7 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. At least 1 of those were confirmed in trans by family testing (PM3_VeryStrong, PMID:31877679, 25333064, 28559085, 24944099, 34781295, 36011402, 32531858, 36909829, 27208204, 37217489). At least one patient with this variant was diagnosed with Usher syndrome, which is highly specific for USH2A-related disorders (PP4, PMID:31877679). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1393629/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense, splice_region

Scores

Splicing: ADA: 0.9728

Clinical Significance

Pathogenic reviewed by expert panel P:12U:3

Conservation

PhyloP100: 7.65

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 5 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.

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
USH2A	NM_206933.4 link	c.11713C>T	p.Arg3905Cys	missense_variant, splice_region_variant	Exon 61 of 72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.11713C>T	p.Arg3905Cys	missense_variant, splice_region_variant	Exon 61 of 72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 link	c.11713C>T	p.Arg3905Cys	missense_variant, splice_region_variant	Exon 61 of 73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000242

AC:

AN:

247752

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134332

show subpopulations

Gnomad AFR exome

AF:

0.0000625

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000239

AC:

AN:

1461572

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727086

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152312

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:3Uncertain:1

Feb 09, 2023

GeneDx

Significance: Pathogenic

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: 25333064, 24944099, 28559085, 27208204, 34781295, 33576794, 32531858, 31877679) -

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3905 of the USH2A protein (p.Arg3905Cys). This variant is present in population databases (rs368675850, gnomAD 0.005%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099, 25333064, 27208204, 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: 236537). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Oct 01, 2016

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 28, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy

Pathogenic:2Uncertain:1

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome

Pathogenic:2

Dec 18, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.11713C>T (p.Arg3905Cys) 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. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.4e-05 in 247752 control chromosomes. c.11713C>T has been reported in the literature as a compound heterozygous genotype in multiple comprehensively genotyped individuals affected with Usher Syndrome (example, Ellingford_2016, Stone_2017, 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. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (P/LP, n=3; VUS, n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 16, 2024

ClinGen Hearing Loss Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.11713C>T variant in USH2A is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 3905 (p.Arg3905Cys). The highest population minor allele frequency in gnomAD v4 is 0.007% (6/75036) in the African / African American population, which meets the ClinGen Hearing Loss VCEP threshold (≤0.007%) for PM2_Supporting. The computational predictor REVEL gives a score of 0.8, which is above the threshold of 0.7, evidence that correlates with impact to USH2A function (PP3). This variant has been detected in at least 6 individuals with Usher syndrome and at least 4 individuals with inherited retinal dystrophy. Of those individuals, 1 was homozygous and 7 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant. At least 1 of those were confirmed in trans by family testing (PM3_VeryStrong, PMID: 31877679, 25333064, 28559085, 24944099, 34781295, 36011402, 32531858, 36909829, 27208204, 37217489). At least one patient with this variant was diagnosed with Usher syndrome, which is highly specific for USH2A-related disorders (PP4, PMID: 31877679). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss Expert Panel: PM2_Supporting, PP3, PM3_VeryStrong, PP4. (ClinGen Hearing Loss VCEP specifications version 2; 10/16/2024). -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1Uncertain:1

Jun 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 23, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinitis pigmentosa 39

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2A

Pathogenic:1

May 27, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4 strong, PM2 moderated, PM3 strong, PP3 supporting -

USH2A-related disorder

Pathogenic:1

Jun 13, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The USH2A c.11713C>T variant is predicted to result in the amino acid substitution p.Arg3905Cys. This variant has been reported in the homozygous and compound heterozygous state in patients with retinal disorders or Usher syndrome (Baux. 2014. PubMed ID: 24944099; Krawitz. 2014. PubMed ID: 25333064; Ellingford. 2016. PubMed ID: 27208204; Stone. 2017. PubMed ID: 28559085; Karali. 2019. PubMed ID: 31877679; Colombo. 2021. PubMed ID: 33576794; Colombo. 2021. PubMed ID: 34781295). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215901725-G-A). This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Jul 24, 2023

Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Clinical significance based on ACMG v2.0 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.055

MutationAssessor

Pathogenic

3.3

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.80

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MVP

0.97

MPC

0.19

ClinPred

0.98

GERP RS

5.2

Varity_R

0.47

gMVP

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.86

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