chr1-215675336-C-T

Position:

chr1-215675336-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PM2PM5BP4_Strong

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. 14/21 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:17U:6

Conservation

PhyloP100: 1.44

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 6 uncertain in NM_206933.4

PM2

Very rare variant in population databases, with high coverage;

PM5

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

BP4

Computational evidence support a benign effect (MetaRNN=0.017341584).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.12575G>A	p.Arg4192His	missense_variant	63/72	ENST00000307340.8	NP_996816.3	O75445-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.12575G>A	p.Arg4192His	missense_variant	63/72	1	NM_206933.4	ENSP00000305941.3		O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.12575G>A	p.Arg4192His	missense_variant	63/73			ENSP00000501296.1		O75445-3

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

GnomAD3 exomes

AF:

0.000589

AC:

147

AN:

249454

Hom.:

AF XY:

0.000541

AC XY:

AN XY:

135010

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000939

Gnomad4 ASJ exome

AF:

0.00972

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000131

Gnomad4 NFE exome

AF:

0.0000746

Gnomad4 OTH exome

AF:

0.000745

GnomAD4 genome

AF:

0.000440

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000349

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.0115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000609

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:17Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2024	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, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249) -
Likely 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)	May 07, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	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; Invitae). 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). 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 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

Likely pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 22, 2022	Criteria applied: PM3_VSTR,PM5,BP4 -
Uncertain significance, no assertion criteria provided	clinical testing	Baylor Genetics	Jan 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	-	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.057%). Protein truncation variants are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.12; 3Cnet: 0.66). 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 Pathogenic according to the recommendation of ACMG/AMP guideline. -

Retinitis pigmentosa

Pathogenic:3Uncertain:1

Likely pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, no assertion criteria provided	research	Sharon lab, Hadassah-Hebrew University Medical Center	Jun 23, 2019	- -
Pathogenic, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Apr 01, 2021	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. -
Uncertain significance, no assertion criteria provided	research	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	Apr 01, 2018	- -

Retinitis pigmentosa 39

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 08, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Counsyl	May 07, 2019	- -

Retinal dystrophy

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 16, 2019	- -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 23, 2023

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. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 280866 control chromosomes in the gnomAD database, including one homozygote. This frequency is not significantly higher than estimated for a pathogenic variant in USH2A causing Usher Syndrome (0.00057 vs 0.011), allowing no conclusion about variant significance. c.12575G>A has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with retinitis pigmentosa or hereditary retinal disorders (Avila-Fernandez_2010, Martin-Merida_2019, Weisschuh_2020, Ganapathi_2022) and this variant co-segregated with the disease (Avila-Fernandez_2010, Martin-Merida_2019). 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. 15 submitters (evaluation after 2014) cite this variant as uncertain significance (n=5), likely pathogenic (n=2) and pathogenic (n=8). Based on the evidence outlined above, the variant was classified as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 11, 2024

- -

USH2A-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2023

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

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2014

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

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

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

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