chr1-215675336-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM5PP5BP4

The NM_206933.4(USH2A):c.12575G>A(p.Arg4192His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,614,098 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4192C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 1 hom. )

Consequence

USH2A
NM_206933.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:19U:5

Conservation

PhyloP100: 1.44

Publications

47 publications found

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 Gene-Disease associations (from GenCC):

Usher syndrome type 2
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Usher syndrome type 2A
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
retinitis pigmentosa 39
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
retinitis pigmentosa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

USH2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_206933.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-215675337-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 281818.Status of the report is reviewed_by_expert_panel, 3 stars.

PP5

Variant 1-215675336-C-T is Pathogenic according to our data. Variant chr1-215675336-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 166434.

BP4

Computational evidence support a benign effect (MetaRNN=0.017341584). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4 link	c.12575G>A	p.Arg4192His	missense_variant	Exon 63 of 72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 link	c.12575G>A	p.Arg4192His	missense_variant	Exon 63 of 72	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1 link	c.12575G>A	p.Arg4192His	missense_variant	Exon 63 of 73			ENSP00000501296.1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.0115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000589

AC:

147

AN:

249454

AF XY:

0.000541

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00871

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000298

AC:

435

AN:

1461796

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.000939

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00972

AC:

254

AN:

26134

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53342

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000746

AC:

AN:

1112004

Other (OTH)

AF:

0.000745

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000440

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41572

American (AMR)

AF:

0.00105

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0115

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68032

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000520

Hom.:

Bravo

AF:

0.000450

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:19Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:5Uncertain:1

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2015

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

USH2A: PM3:Very Strong, PM5, PM2:Supporting, BP4 -

Feb 10, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, 23591405, 26427457, 28131284, 26880948, 28559085, 21151602, 22334370, 27596865, 28118666, 30217765, 32326409, 31980526, 32036094, 32581362, 26806561, 25412400, 28041643, 26927203, 29276052, 31049658, 31736247, 32269941, 31456290, 28805479, 27160483, 20507924, 22135276, 34327195, 32675063, 28894305, 36524988, 31964843, 36460718, 36785559, 37217489, 33749171, 37734845, 34906470, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249, 23940504, 27460420) -

Jun 18, 2019

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

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 histidine, which is basic and polar, at codon 4192 of the USH2A protein (p.Arg4192His). This variant is present in population databases (rs199605265, gnomAD 0.9%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild or late onset deafness and/or nonsyndromic retinal disease (PMID: 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305; internal data). 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: 166434). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt USH2A protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A

Pathogenic:3Uncertain:1

Feb 19, 2024

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.057%). Predicted Consequence/Location: The majority of the known disease-causing variants of this gene are variants expected to result in premature termination of the protein. In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.12 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.66 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000166434 /3billion dataset). A different missense change at the same codon (p.Arg4192Cys) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000281818 /PMID: 23940504). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Jun 22, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_VSTR,PM5,BP4 -

Jan 26, 2022

Baylor Genetics

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2024

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Retinitis pigmentosa

Pathogenic:3Uncertain:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:research

- -

Apr 01, 2021

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg4192His 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: PS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab. -

Retinitis pigmentosa 39

Pathogenic:2Uncertain:1

May 07, 2019

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The USH2A c.12575G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PS1, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. -

Feb 08, 2019

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:2

Oct 31, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal dystrophy

Pathogenic:2

Aug 16, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2023

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Usher syndrome

Pathogenic:1

Feb 19, 2025

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.12575G>A (p.Arg4192His) 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 benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00059 in 249454 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00059 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa, hereditary retinal disorders, and/or mild or late onset hearing loss (e.g. Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022, Labcorp Genetics (formerly Invitae)) and this variant co-segregated with disease (Avila-Fernandez_2010, Martin-Merida_2019). These data indicate that the variant is very likely to be associated with disease. Additionally, a different variant affecting the same codon has been classified as pathogenic by our lab (c.12574C>T, p.Arg4192Cys), supporting the critical relevance of codon 4192 to USH2A protein function. The following publications have been ascertained in the context of this evaluation (PMID: 21151602, 35672425, 30902645, 32531858). ClinVar contains an entry for this variant (Variation ID: 166434). Based on the evidence outlined above, the variant was classified as pathogenic. -

USH2A-related disorder

Pathogenic:1

Aug 02, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The USH2A c.12575G>A variant is predicted to result in the amino acid substitution p.Arg4192His. This variant has been reported in the compound heterozygous state as causative for retinitis pigmentosa (RP) and Usher syndrome type 2 (Lenassi et al. 2015. PubMed ID: 25649381; Neveling et al. 2012. PubMed ID: 22334370; Avila-Fernandez et al. 2010. PubMed ID: 21151602). At PreventionGenetics, we have seen this variant either in the homozygous state or along with a second causative variant in several unrelated patients (internal data). This variant is reported in 0.89% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, including one homozygote (http://gnomad.broadinstitute.org/variant/1-215848678-C-T), which is relatively common for disease causing variant. The majority of submitters to ClinVar interpret this variant as pathogenic or likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/166434/). Given the evidence, we interpret c.12575G>A (p.Arg4192His) as pathogenic. -

not specified

Uncertain:1

Jul 16, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The Arg4192His variant in USH2A has been reported in four individuals with autosomal recessive retinitis pigmentosa (McGee 2010, Avila-Fernandez 2010, Tucker 2013). Three of these individuals were homozygous or compound heterozygous, and one was only reported to be heterozygous for this variant but there was no information about a second variant. The Arg4192His variant has been identified in 0.023% (2/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs199605265). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The arginine (Arg) at position 4192 is not conserved in mammals or evolutionary distant species, including many species carrying a histidine (His) at this position, raising the possibility that a change at this position may be tolerated. Additional computational prediction tools suggest that the Arg4192His variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, while the clinical significance of the Arg4192His variant is uncertain, these data suggest that is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.070

Eigen

Benign

-0.18

Eigen_PC

Benign

0.0049

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.55

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.78

MutationAssessor

Benign

1.7

PhyloP100

1.4

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.1

REVEL

Benign

0.12

Sift

Benign

0.15

Sift4G

Benign

0.38

Polyphen

0.013

Vest4

0.066

MVP

0.91

MPC

0.048

ClinPred

0.020

GERP RS

4.2

Varity_R

0.088

gMVP

0.68

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over