1-216325412-T-G

Position:

chr1-216325412-T-G

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PP1_StrongPP3PP4PM3PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID:15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID:10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP1_S, PM3_VS, PP4, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA262054/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

9

6

4

Clinical Significance

Pathogenic reviewed by expert panel P:14

Conservation

PhyloP100: 7.67

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 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.

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.1036A>C	p.Asn346His	missense_variant	6/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A	NM_007123.6 linkuse as main transcript	c.1036A>C	p.Asn346His	missense_variant	6/21		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.1036A>C	p.Asn346His	missense_variant	6/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.1036A>C	p.Asn346His	missense_variant	6/21	1		ENSP00000355909.3		O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.1036A>C	p.Asn346His	missense_variant	6/73			ENSP00000501296.1		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

9

AN:

152148

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

17

AN:

250972

Hom.:

0

AF XY:

0.0000885

AC XY:

12

AN XY:

135618

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:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000677

AC:

99

AN:

1461660

Hom.:

0

Cov.:

31

AF XY:

0.0000564

AC XY:

41

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000818

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000592

AC:

9

AN:

152148

Hom.:

0

Cov.:

32

AF XY:

0.0000673

AC XY:

5

AN XY:

74334

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000461

Hom.:

0

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

0

ESP6500EA

AF:

0.000116

AC:

1

ExAC

AF:

0.0000988

AC:

12

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 19, 2023	This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 346 of the USH2A protein (p.Asn346His). This variant is present in population databases (rs369522997, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 10729113, 19129697, 24160897, 25097241, 25521520, 26969326, 28559085, 29343940). 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: 48347). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -

Usher syndrome type 2A

Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Usher syndrome type 2A (MIM#276901). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (19 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (7 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0600 - Variant is located in the annotated lamin N-terminal domain VI (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reviewed as pathogenic by an expert panel in ClinVar and has been observed in many individuals with Usher syndrome (PMID: 28944237). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Retinitis pigmentosa 39

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Aug 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	May 29, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2021	- -

Usher syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Sep 14, 2018

The allele frequency of the p.Asn346His variant in the USH2A gene is 0.016% (20/126318) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_Supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Usher syndrome (PM2_Supporting). The p.Asn346His variant in USH2A has been reported to segregate with hearing loss in at least 7 families including 13 family members (PP1_S; 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). This variant has been detected in patients with hearing loss in trans with at least 4 pathogenic or suspected-pathogenic variants (PM3_VS; PMID: 15241801, 24160897, 22135276, 26969326). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 10729113, 15241801, 17405132, 25521520, 24160897, 22135276). Computational prediction tools and conservation analysis suggest that the p.Asn346His variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2_Supporting, PP1_S, PM3_VS, PP4, PP3. -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 26, 2012

The Asn346His variant in USH2A has been reported in 10 individuals with type II Usher syndrome (Weston 2000, Baux 2007, Dreyer 2000, Ouyang 2004, Pennings 2004, Vastinsalo 2012). 3/10 of these individuals were compound heterozygous. The As n residue at position 346 is highly conserved. This variant has been identified in 0.01% (1/8600) of European American chromosomes from a broad population by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although t his variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In summary, this variant i s likely pathogenic, though additional studies are required to fully establish i ts clinical significance. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

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

Apr 01, 2021

The p.Asn346His 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, PM3, PP1, PP3, PP4. Based on this evidence we have classified this variant as Likely Pathogenic. 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

Uncertain

0.43

BayesDel_addAF

Benign

-0.064

T

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

23

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

0.99

D

LIST_S2

Benign

0.82

T;T

M_CAP

Pathogenic

0.37

D

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.49

D

MutationAssessor

Pathogenic

3.2

M;M

PrimateAI

Benign

0.48

T

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.81

MVP

0.96

MPC

0.24

ClinPred

0.72

D

GERP RS

5.4

Varity_R

0.84

gMVP

0.70

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.

Other links and lift over

dbSNP: rs369522997; hg19: chr1-216498754;