chr1-216289392-C-A

Position:

chr1-216289392-C-A

Variant summary

Our verdict is Pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PP4PP1PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) 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 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID:22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607*, p.Glu767Serfs*21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID:22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID:36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA1396372/MONDO:0019501/005

Frequency

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

Exomes 𝑓: 0.000058 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

13

4

2

Clinical Significance

Pathogenic reviewed by expert panel P:8U:1

Conservation

PhyloP100: 6.80

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 6 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.

PP1

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/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.1859G>T	p.Cys620Phe	missense_variant	11/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 linkuse as main transcript	c.1859G>T	p.Cys620Phe	missense_variant	11/21		NP_009054.6	O75445-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.1859G>T	p.Cys620Phe	missense_variant	11/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1859G>T	p.Cys620Phe	missense_variant	11/21	1		ENSP00000355909.3		O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1859G>T	p.Cys620Phe	missense_variant	11/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

3

AN:

152182

Hom.:

0

Cov.:

32

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

GnomAD3 exomes

AF:

0.0000159

AC:

4

AN:

251316

Hom.:

0

AF XY:

0.0000221

AC XY:

3

AN XY:

135814

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000582

AC:

85

AN:

1461622

Hom.:

0

Cov.:

31

AF XY:

0.0000591

AC XY:

43

AN XY:

727112

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:

0.0000747

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

3

AN:

152182

Hom.:

0

Cov.:

32

AF XY:

0.0000134

AC XY:

1

AN XY:

74350

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:

0.0000227

ExAC

AF:

0.0000165

AC:

2

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 19, 2020	The p.Cys620Phe variant in USH2A has been reported in at least 2 individuals with Usher syndrome, including two compound heterozygotes (Le Quesne Stabej 2012). It has also been reported in ClinVar (Variation ID 549981). The p.Cys620Phe variant has been identified in 0.004% (5/129062) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). Another variant at the same position, p.Cys620Tyr has been reported in a homozygous individual with Usher syndrome (Baux 2014). In addition, an in vitro functional study suggests that this variant results in a failure of the Usherin peptide to co-immunoprecipitate fibronectin, which may indicate a disruption of normal protein function (Bhattacharya 2005); however, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses also suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive Usher syndrome. ACMG/AMP criteria applied: PM3_Strong, PM2, PP3, PP4, PS3_Supporting. -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Oct 24, 2023	The c.1859G>T in USH2A is a missense variant predicted to cause a substitution of cysteine to phenylalanine at amino acid 620 (p.Cys620Phe) . The highest population minor allele frequency in gnomAD v2.1.1 is 0.004% (5/129062) 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 0.974 (PP3). This variant has been detected in at least four probands with other pathogenic or suspected-pathogenic variants confirmed in trans (4.0 PM3_Very Strong points; PMID: 22135276, 33089500, 36011334). The probands harbored these variants in USH2A: p.Trp1607, p.Glu767Serfs21, p.Cys759Phe, p.Gly3195*. At least one patient displayed features of hearing loss and retinitis pigmentosa, which is highly specific for USH2A and Usher syndrome (PP4; PMID: 22135276). The variant has been reported to segregate with AR Usher syndrome in one affected family member from one family (PP1; PMID: 36011334). In summary, this variant meets the criteria to be classified as pathogenic for AR Usher syndrome based on ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP; PM2_Supporting, PP3, PM3_Very Strong, PP4, PP1. (The ClinGen Hearing Loss VCEP Specifications Version 2; 06/27/2023). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2023	Variant summary: USH2A c.1859G>T (p.Cys620Phe) 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 1.6e-05 in 251316 control chromosomes (gnomAD). c.1859G>T has been reported in the literature in multiple individuals affected with Usher Syndrome (examples: Feenstra_2002, Stabej_2012, Molina-Ramirez_2020, Hagag_USH2A_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated this variant abolishes fibronectin/collagen interaction (example: Bhattacharya_2005). The following publications have been ascertained in the context of this evaluation (PMID: 22135276 , 32176120, 31266775, 33089500, 36011334, 16114888). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic (n=5) and VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	Oct 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	Feb 01, 2019	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 620 of the USH2A protein (p.Cys620Phe). This variant is present in population databases (rs758571672, gnomAD 0.004%). This missense change has been observed in individuals with Usher syndrome (PMID: 16963483, 22135276; Invitae). ClinVar contains an entry for this variant (Variation ID: 549981). 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%. Experimental studies have shown that this missense change affects USH2A function (PMID: 16114888). This variant disrupts the p.Cys620 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 24944099), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 10, 2024

- -

USH2A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 23, 2022

The USH2A c.1859G>T variant is predicted to result in the amino acid substitution p.Cys620Phe. This variant has been reported as causative for Usher syndrome (Le Quesne Stabej et al. 2012. PubMed ID: 22135276; Molina-Ramírez et al. 2020. PubMed ID: 32176120). Functional studies have suggested that this variant does not affect collagen binding (Bhattacharya et al. 2004. PubMed ID: 14676276), but abolishes fibronectin binding (Bhattacharya and Cosgrove. 2005. PubMed ID: 16114888). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216462734-C-A). This variant is interpreted as likely pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

May 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.46

D

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

26

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Benign

0.85

T;T

M_CAP

Pathogenic

0.71

D

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

4.8

H;H

PrimateAI

Uncertain

0.72

T

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.95

Loss of methylation at K621 (P = 0.0756);Loss of methylation at K621 (P = 0.0756);

MVP

0.96

MPC

0.27

ClinPred

0.97

D

GERP RS

5.2

Varity_R

0.99

gMVP

0.97

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: rs758571672; hg19: chr1-216462734; COSMIC: COSV105883095;