rs121912600

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000307340.8(USH2A):​c.1256G>T​(p.Cys419Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C419R) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000097 ( 0 hom. )

Consequence

USH2A
ENST00000307340.8 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:25U:1

Conservation

PhyloP100: 5.86
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a domain Laminin N-terminal (size 246) in uniprot entity USH2A_HUMAN there are 107 pathogenic changes around while only 17 benign (86%) in ENST00000307340.8
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-216324241-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1913735.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.956
PP5
Variant 1-216324240-C-A is Pathogenic according to our data. Variant chr1-216324240-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216324240-C-A is described in Lovd as [Pathogenic]. Variant chr1-216324240-C-A is described in Lovd as [Pathogenic]. Variant chr1-216324240-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
USH2ANM_206933.4 linkuse as main transcriptc.1256G>T p.Cys419Phe missense_variant 7/72 ENST00000307340.8 NP_996816.3
USH2ANM_007123.6 linkuse as main transcriptc.1256G>T p.Cys419Phe missense_variant 7/21 NP_009054.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkuse as main transcriptc.1256G>T p.Cys419Phe missense_variant 7/721 NM_206933.4 ENSP00000305941 P1O75445-1
USH2AENST00000366942.3 linkuse as main transcriptc.1256G>T p.Cys419Phe missense_variant 7/211 ENSP00000355909 O75445-2
USH2AENST00000674083.1 linkuse as main transcriptc.1256G>T p.Cys419Phe missense_variant 7/73 ENSP00000501296 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000400
AC:
10
AN:
250184
Hom.:
0
AF XY:
0.0000517
AC XY:
7
AN XY:
135310
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:
0.0000884
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000972
AC:
142
AN:
1461168
Hom.:
0
Cov.:
31
AF XY:
0.000106
AC XY:
77
AN XY:
726860
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000123
Gnomad4 OTH exome
AF:
0.0000829
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74320
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000974
Hom.:
0
Bravo
AF:
0.0000491
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000494
AC:
6
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:25Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:8
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Apr 21, 2016- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsJan 12, 2016- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 419 of the USH2A protein (p.Cys419Phe). This variant is present in population databases (rs121912600, gnomAD 0.009%). This missense change has been observed in individual(s) with Usher syndrome (PMID: 10729113, 15043528, 15241801, 22334370, 24265693, 24498627, 28041643, 28559085). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Dutch ancestry (PMID: 15241801). ClinVar contains an entry for this variant (Variation ID: 2359). 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 submitterclinical testingGeneDxMay 24, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24944099, 22334370, 33576794, 32853555, 34758253, 24265693, 10729113, 15043528, 22135276, 28559085, 31980526, 32176120, 33360097, 32037395, 36011334, 36284670, 34781295, 35266249, 28761320, 36819107, 20301515, 37237007, 25999674, 28041643, 18641288, 24498627, 16963483, 15015129, 15325563, 37108761, 25649381) -
Usher syndrome type 2A Pathogenic:6
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, no assertion criteria providedliterature onlyOMIMApr 01, 2004- -
Pathogenic, no assertion criteria providedclinical testingCounsylFeb 08, 2017- -
Pathogenic, no assertion criteria providedclinical testingGenomics England Pilot Project, Genomics England-- -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+Sep 01, 2016- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinitis pigmentosa 39 Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 01, 2024- -
Pathogenic, no assertion criteria providedclinical testingCounsylFeb 08, 2017- -
Pathogenic, criteria provided, single submitterresearchOcular Genomics Institute, Massachusetts Eye and EarApr 08, 2021The USH2A c.1256G>T 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: PS4, PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabNov 04, 2023- -
Retinal dystrophy Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJul 17, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, Univ. Regensburg, Univ. RegensburgJan 01, 2020- -
USH2A-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitterresearchUNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill-USH2A c.1256G>T (p.C419F) has been described as a pathogenic variant and has been reported in the homozygous or compound heterozygous state in multiple individuals with Usher syndrome type IIA and nonsyndromic retinitis pigmentosa (PMID: 15015129; 15241801;15325563; 10729113; 22135276; 24944099; 25999674). -
Pathogenic, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017Across a selection of the available literature, the USH2A c.1256G>T (p.Cys419Phe) missense variant has been identified in a homozygous state in two patients with Usher syndrome, in a compound heterozygous state in 13 patients of whom ten were diagnosed with Usher syndrome and three with retinitis pigmentosa (RP), and in a heterozygous state in 16 patients of whom ten were diagnosed with Usher syndrome and six with RP (Weston et al. 2000; Van Wijk et al. 2004; Seyedahmadi et al. 2004; Sandberg et al. 2008; Neveling et al. 2012; Le Quesne Stabe et al. 2012; Eisenberger et al. 2013; Besnard et al. 2014; Cremers et al. 2014; Pennings et al. 2004; Van Huet et al. 2015). The p.Cys419Phe variant is a possible Dutch founder variant as deduced by haplotype analysis by Pennings et al. (2004). The p.Cys419Phe variant was absent in at least 1000 controls and is reported at a frequency of 0.000093 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the collective evidence, the p.Cys419Phe variant is classified as pathogenic for USH2A-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Usher syndrome Pathogenic:1Uncertain:1
Uncertain significance, no assertion criteria providedresearchNIHR Bioresource Rare Diseases, University of CambridgeJan 01, 2015- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 09, 2019Variant summary: USH2A c.1256G>T (p.Cys419Phe) results in a non-conservative amino acid change located in the Laminin, N-terminal domain (IPR008211) 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 4e-05 in 250184 control chromosomes. c.1256G>T has been reported in the literature in multiple individuals affected with Usher syndrome and/or Retinitis Pigmentosa (example, Weston_2000, Neveling_2012, Eisenberger_2013, Stone_2017). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Pathogenic, n=5, VUS, n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 27, 2021- -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineOct 28, 2010The Cys419Phe variant in USH2A has been reported in 16/246 probands with Usher s yndrome Type 2 and was absent from 380 control chromosomes (p<0.0001, Weston 200 0, Pennings 2004, Seyedahmadi 2004). Many of these probands were homozygous or c ompound heterozygous. In addition, this variant is thought to be a founder mutat ion in the Dutch population (Pennings 2004). In summary, this variant meets our criteria to be classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Pathogenic
0.26
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.69
D;.
Eigen
Pathogenic
0.90
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.82
T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Uncertain
0.30
D
MutationAssessor
Pathogenic
3.8
H;H
MutationTaster
Benign
1.0
A;A;A
PrimateAI
Uncertain
0.58
T
PROVEAN
Pathogenic
-7.6
D;D
REVEL
Uncertain
0.61
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.97
MVP
0.96
MPC
0.27
ClinPred
0.98
D
GERP RS
5.4
Varity_R
0.98
gMVP
0.85

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.

Other links and lift over

dbSNP: rs121912600; hg19: chr1-216497582; API