1-216325499-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_206933.4(USH2A):​c.949C>A​(p.Arg317Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000421 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

USH2A
NM_206933.4 synonymous

Scores

2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:23

Conservation

PhyloP100: 1.57
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 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-216325499-G-T is Pathogenic according to our data. Variant chr1-216325499-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-216325499-G-T is described in Lovd as [Likely_pathogenic]. Variant chr1-216325499-G-T is described in Lovd as [Pathogenic]. Variant chr1-216325499-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
USH2ANM_206933.4 linkc.949C>A p.Arg317Arg synonymous_variant Exon 6 of 72 ENST00000307340.8 NP_996816.3 O75445-1
USH2ANM_007123.6 linkc.949C>A p.Arg317Arg synonymous_variant Exon 6 of 21 NP_009054.6 O75445-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
USH2AENST00000307340.8 linkc.949C>A p.Arg317Arg synonymous_variant Exon 6 of 72 1 NM_206933.4 ENSP00000305941.3 O75445-1
USH2AENST00000366942.3 linkc.949C>A p.Arg317Arg synonymous_variant Exon 6 of 21 1 ENSP00000355909.3 O75445-2
USH2AENST00000674083.1 linkc.949C>A p.Arg317Arg synonymous_variant Exon 6 of 73 ENSP00000501296.1 O75445-3

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
32
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000279
AC:
7
AN:
250788
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135506
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:
0.0000618
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000445
AC:
65
AN:
1461598
Hom.:
0
Cov.:
31
AF XY:
0.0000468
AC XY:
34
AN XY:
727106
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:
0.0000549
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152122
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74300
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000115
Hom.:
0
Bravo
AF:
0.0000227
EpiCase
AF:
0.0000546
EpiControl
AF:
0.0000593

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:7
Feb 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

USH2A: PM3:Very Strong, PVS1, PM2 -

Apr 01, 2016
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 26, 2017
Knight Diagnostic Laboratories, Oregon Health and Sciences University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 05, 2020
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Non-canonical splice site variant demonstrated to result in loss-of-function (Vache et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27957503, 15043528, 15015129, 30904819, 20513143, 26927203, 24944099, 23891399, 28944237, 15241801, 15325563, 21569298, 18273898, 16963483, 25575603, 30609409) -

Oct 19, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects codon 317 of the USH2A mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the USH2A protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs111033272, gnomAD 0.006%). This variant has been observed in individual(s) with Usher syndrome type IIa or nonsydromic retinitis pigmentosa (PMID: 15241801, 20513143, 21569298, 26927203). 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: 2358). Studies have shown that this variant results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 20513143). For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A Pathogenic:7
Apr 01, 2004
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 29, 2021
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was classified as: Pathogenic. -

Jan 10, 2025
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 2019
Counsyl
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Oct 07, 2024
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was in trans with USH2A c.1172G>T in a patient presenting with clinical signs that correspond with Usher syndrome. This variant is not present in a homozygous state in population database gnomAD (v4.1.0). It was reported as pathogenic multiple times in ClinVar. It was featured in multiple articles concerning Usher syndrome type 2 (PMID 20513143, 27460420, 15241801, 26927203). Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinitis pigmentosa 39 Pathogenic:3
Mar 08, 2024
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 04, 2023
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 24, 2019
Counsyl
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2
May 09, 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: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2 Pathogenic:1
Jan 09, 2020
Molecular Genetics Laboratory, Institute for Ophthalmic Research
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Blindness;C1840457:Retinal pigment epithelial atrophy;C4520679:Abnormal macular morphology;C4551714:Rod-cone dystrophy;C4551715:Pigmentary retinopathy Pathogenic:1
Jan 01, 2017
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Rare genetic deafness Pathogenic:1
Nov 19, 2012
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg317Arg (NM_206933.2 c.949C>A) variant in USH2A has been reported in 9 i ndividuals with Usher syndrome (Pennings 2004, Seyedahmadi 2004, Cremers 2007, D reyer 2008, Vache 2010, Bonnet 2011). A second variant in USH2A was found in tr ans in at least 3 of these individuals (Pennings 2004, Vache 2010, Bonnet 2011). This variant has also been reported in ClinVar (Variation ID#2358) as pathogeni c. mRNA studies show that this variant leads to abnormal splicing and a frameshi ft (Vache 2010). This variant has been identified in (8/126206) of European chro mosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP rs111033272). Although this variant has been seen in the general pop ulation, its frequency is low enough to be consistent with a recessive carrier f requency. In summary, this variant meets criteria to be classified as pathogenic for Usher syndrome in an autosomal recessive manner based upon functional evide nce and its occurrence in individuals with this disease. ACMG/AMP Criteria appli ed: PVS1, PM2, PM3, PP5. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.47
CADD
Benign
18
DANN
Benign
0.42

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.73
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.73
Position offset: -1

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: rs111033272; hg19: chr1-216498841; API