1-216084853-C-T

Position:

chr1-216084853-C-T

Variant summary

Our verdict is Pathogenic. Variant got 7 ACMG points: 7P and 0B. PM3PP1_StrongPP3

This summary comes from the ClinGen Evidence Repository: The c.5012G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 1671 (p.Gly1671Asp). The highest population minor allele frequency in gnomAD v4 is 0.04% (51/91074 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.906, 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 10 individuals with retinitis pigmentosa or inherited retinal disease. Of those individuals, 9 were homozygous and 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.4251+1G>T, 5 PM3 points, PMID:26667666, 32581362, 33749171, 38219857, PM3_VeryStrong). Internal evidence from one laboratory indicates that this variant has been observed in trans with a likely pathogenic missense variant in an individual with optic neuropathy, night blindness, and sensorineural hearing loss and homozygous in one individual with hearing loss and hyperopia (Personal communication, SCV001789135.4). This suggests that there may be phenotypic variability with some individuals presenting with isolated retinal dystrophy, and some presenting with hearing loss and signs and/or symptoms of retinal dystrophy. Of note, many of these individuals were of South Asian ancestry, consistent with the population evidence from gnomAD (PMID:38219857). The variant has been reported to segregate with inherited retinal disease in 3 affected family members from 2 families (PP1_Strong; PMID:38219857). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive USH2A-related inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_VeryStrong, PP1_Strong. (ClinGen Hearing Loss VCEP specifications version 2, 02.27.2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA185105/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:9U:2

Conservation

PhyloP100: 6.54

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:

USH2A-AS2 (HGNC:40605): (USH2A antisense RNA 2)

USH2A-AS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 7 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.5012G>A	p.Gly1671Asp	missense_variant	25/72	ENST00000307340.8	NP_996816.3	O75445-1
USH2A-AS2	NR_125992.1 link	n.266-1869C>T		intron_variant
USH2A-AS2	NR_125993.1 link	n.137-1869C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.5012G>A	p.Gly1671Asp	missense_variant	25/72	1	NM_206933.4	ENSP00000305941.3		O75445-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000479

AC:

AN:

250622

Hom.:

AF XY:

0.0000738

AC XY:

AN XY:

135460

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:

0.000392

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1460998

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726808

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:

0.000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000577

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9Uncertain:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 12, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 1671 of the USH2A protein (p.Gly1671Asp). This variant is present in population databases (rs727505116, gnomAD 0.04%). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 26667666, 28041643, 32581362). ClinVar contains an entry for this variant (Variation ID: 179773). 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	GeneDx	Aug 19, 2024	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: 22135276, 26667666, 28041643, 32637036, 31456290, 31964843, 32581362, 34426522, 31816670, 32176120, 33749171, 38219857) -

Usher syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2022	Variant summary: USH2A c.5012G>A (p.Gly1671Asp) results in a non-conservative amino acid change located in the Laminin G domain (IPR001791) 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 4.8e-05 in 250622 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (4.8e-05 vs 0.011), allowing no conclusion about variant significance. c.5012G>A has been reported in the literature in compound heterozygous and homozygous individuals affected with retinitis pigmentosa (Ge_2015, Carss_2017, Sharon_2020, Yohe_2019, Molina-Ramirez_2020, Yu_2020, Turro_2020, Sheck_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=2) and likely pathogenic (n=3), including one expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) classified this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation	Dec 31, 2022	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 21, 2024

- -

Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen Hearing Loss Variant Curation Expert Panel

Feb 27, 2024

The c.5012G>A variant in USH2A is a missense variant predicted to cause substitution of glycine by aspartic acid at amino acid 1671 (p.Gly1671Asp). The highest population minor allele frequency in gnomAD v4 is 0.04% (51/91074 alleles) in the South Asian population (PM2_Supporting, BS1, and BA1 are not met). The computational predictor REVEL gives a score of 0.906, 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 10 individuals with retinitis pigmentosa or inherited retinal disease. Of those individuals, 9 were homozygous and 1 was compound heterozygous for the variant and a pathogenic or likely pathogenic variant with phase unknown (c.4251+1G>T, 5 PM3 points, PMID:26667666, 32581362, 33749171, 38219857, PM3_VeryStrong). Internal evidence from one laboratory indicates that this variant has been observed in trans with a likely pathogenic missense variant in an individual with optic neuropathy, night blindness, and sensorineural hearing loss and homozygous in one individual with hearing loss and hyperopia (Personal communication, SCV001789135.4). This suggests that there may be phenotypic variability with some individuals presenting with isolated retinal dystrophy, and some presenting with hearing loss and signs and/or symptoms of retinal dystrophy. Of note, many of these individuals were of South Asian ancestry, consistent with the population evidence from gnomAD (PMID:38219857). The variant has been reported to segregate with inherited retinal disease in 3 affected family members from 2 families (PP1_Strong; PMID: 38219857). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive USH2A-related inherited retinal dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PP3, PM3_VeryStrong, PP1_Strong. (ClinGen Hearing Loss VCEP specifications version 2, 02.27.2024). -

USH2A-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 11, 2022

The USH2A c.5012G>A variant is predicted to result in the amino acid substitution p.Gly1671Asp. This variant has been reported in the homozygous or compound heterozygous states in patients with retinitis pigmentosa (Ge et al. 2015. PubMed ID: 26667666; Table S2, Carss et al. 2017. PubMed ID: 28041643; Table S2, Sharon et al. 2020. PubMed ID: 31456290). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216258195-C-T). This variant is interpreted as likely pathogenic. -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 08, 2014

The Gly1671Asp variant in USH2A has been previously identified in two Indian ind ividuals with Usher syndrome (Le Quesne Stabej 2012, personal communication), th ough one individual did not carry a second USH2A variant and the second individu al carried two other USH2A variants and it was not clear which of the three vari ants was contributing to the disease. This variant has not been identified in la rge population databases; however, there is insufficient data to assess the freq uency of this variant in Indian control populations. Computational prediction t ools and conservation analyses suggest that the Gly1671Asp variant may impact th e protein, though this information is not predictive enough to determine pathoge nicity. In summary, the clinical significance of the Gly1671Asp variant is uncer tain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.43

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.92

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.9

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-4.5

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.87

Gain of ubiquitination at K1674 (P = 0.1317);

MVP

0.82

MPC

0.26

ClinPred

0.95

GERP RS

4.9

Varity_R

0.98

gMVP

0.96

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.

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