rs375668376

Positions:

chr1-216073292-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4PP1PP3PM2_SupportingPS4PM3_Strong

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Gly1861Ser variant in USH2A is 0.017% (3/17184) of East Asian 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 hearing loss (PM2_P). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). This variant has been detected in 4 patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3_S; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID:26310143). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID:PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). Computational prediction tools and conservation analysis suggest that the p.Gly1861Ser 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: PS4, PM2_P, PP3, PM3_S, PP1, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA262105/MONDO:0019501/005

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

11

5

3

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 4.59

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 12 ACMG points.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

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.5581G>A	p.Gly1861Ser	missense_variant	28/72	ENST00000307340.8	NP_996816.3
USH2A-AS2	NR_125992.1 linkuse as main transcript	n.136+692C>T		intron_variant, non_coding_transcript_variant
USH2A-AS2	NR_125993.1 linkuse as main transcript	n.136+692C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.5581G>A	p.Gly1861Ser	missense_variant	28/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A-AS2	ENST00000446411.5 linkuse as main transcript	n.136+692C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

2

AN:

151370

Hom.:

0

Cov.:

32

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000197

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

3

AN:

250216

Hom.:

0

AF XY:

0.0000222

AC XY:

3

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

4

AN:

1461486

Hom.:

0

Cov.:

31

AF XY:

0.00000413

AC XY:

3

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

2

AN:

151370

Hom.:

0

Cov.:

32

AF XY:

0.00

AC XY:

0

AN XY:

73866

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000197

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.000270

AC:

1

ALSPAC

AF:

0.00

AC:

0

ESP6500AA

AF:

0.000227

AC:

1

ESP6500EA

AF:

0.00

AC:

0

ExAC

AF:

0.00000824

AC:

1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Usher syndrome

Pathogenic:2

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 14, 2018	The allele frequency of the p.Gly1861Ser variant in USH2A is 0.017% (3/17184) of East Asian 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 hearing loss (PM2_P). This variant was found to have a statistically higher prevalence in affected individuals over controls (PS4; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). This variant has been detected in 4 patients with hearing loss in trans with pathogenic or suspected-pathogenic variants (PM3_S; PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). The variant has been reported to segregate with hearing loss in one affected family member (PP1, PMID: 26310143). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: PMIDs: 26310143, 26338283, 23737954, Partners LMM internal data SCV000065557.5). Computational prediction tools and conservation analysis suggest that the p.Gly1861Ser 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: PS4, PM2_P, PP3, PM3_S, PP1, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: USH2A c.5581G>A (p.Gly1861Ser) 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 1.2e-05 in 250216 control chromosomes (gnomAD). c.5581G>A has been reported in the literature in the compound heterozygous state in multiple individuals affected with Usher Syndrome, including cases where it was confirmed to be in trans with a pathogenic variant (e.g. Huang_2013, Jiang_2015, Huang_2015, Zheng_2015, Guan_2021). 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. The following publications have been ascertained in the context of this evaluation (PMID: 34416374, 25356976, 23737954, 26338283, 26310143). Four submitters, including the ClinGen Hearing Loss Variant Curation Expert Panel, have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 19, 2023	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1861 of the USH2A protein (p.Gly1861Ser). This variant is present in population databases (rs375668376, gnomAD 0.02%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 23737954, 25356976, 26310143, 26338283, 29625443). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48535). 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. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Classified as pathogenic by the ClinGen Hearing Loss Expert Panel (ClinVar SCV000840514.3; PMID: 30311386); This variant is associated with the following publications: (PMID: 34416374, 30311386, 25356976, 30948794, 29625443, 26338283, 26310143, 23737954, 32675063, 32893482, 35314707, 32188678) -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 26, 2017

- -

Retinitis pigmentosa 39

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 22, 2023

- -

Rare genetic deafness

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 07, 2011

The Gly1861Ser variant in USH2A has been identified by our laboratory in one pat ient with Usher syndrome who was a compound heterozygote with a pathogenic USH2A variant (c.8559-2A>G). Therefore, this variant is likely pathogenic. -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 13, 2018

- -

USH2A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

The USH2A c.5581G>A variant is predicted to result in the amino acid substitution p.Gly1861Ser. This variant has been reported along with a second potentially causative variant including at least one truncating variant in patients with retinitis pigmentosa, nonsyndromic hearing loss, and Usher syndrome (Huang. 2013. PubMed ID: 23737954; Chen. 2020. PubMed ID: 32893482; Supplemental, Gao. 2021. PubMed ID: 32188678; Table S3, Guan. 2021. PubMed ID: 34416374; Table S5, Huang. 2015. PubMed ID: 25356976; Zheng. 2015. PubMed ID: 26310143). This variant is reported in 0.016% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-216246634-C-T) and is interpreted as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/48535/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.16

D

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

24

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

D

LIST_S2

Uncertain

0.87

D

M_CAP

Pathogenic

0.91

D

MetaRNN

Pathogenic

0.95

D

MetaSVM

Pathogenic

1.1

D

MutationAssessor

Pathogenic

3.2

M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

T

PROVEAN

Uncertain

-4.0

D

REVEL

Pathogenic

0.79

Sift

Pathogenic

0.0

D

Sift4G

Pathogenic

0.0

D

Polyphen

1.0

D

Vest4

0.93

MVP

0.75

MPC

0.23

ClinPred

1.0

D

GERP RS

5.9

Varity_R

0.96

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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: rs375668376; hg19: chr1-216246634;