rs397518041

Positions:

chr1-215845898-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_206933.4(USH2A):c.8981G>A(p.Trp2994Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000552 in 1,613,758 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

USH2A
NM_206933.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: -0.263

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 Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-215845898-C-T is Pathogenic according to our data. Variant chr1-215845898-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215845898-C-T is described in Lovd as [Pathogenic]. Variant chr1-215845898-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.8981G>A	p.Trp2994Ter	stop_gained	45/72	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.8981G>A	p.Trp2994Ter	stop_gained	45/72	1	NM_206933.4	ENSP00000305941	P1	O75445-1
USH2A	ENST00000674083.1 linkuse as main transcript	c.8981G>A	p.Trp2994Ter	stop_gained	45/73			ENSP00000501296		O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251094

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0000615

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461600

Hom.:

Cov.:

AF XY:

0.0000646

AC XY:

AN XY:

727106

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000737

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74306

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000558

Hom.:

Bravo

AF:

0.0000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinitis pigmentosa 39

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2024	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.8981G>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: PVS1, PM2, PP3. Based on this evidence we have classified this variant as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -

Usher syndrome type 2A

Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 04, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 01, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 45 of 72). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. More than 10 NMD-predicted variants have been reported as likely pathogenic/pathogenic (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in unrelated patients with Usher syndrome and retinitis pigmentosa (PMIDs: 19881469, 28041643), and as pathogenic in ClinVar. (P) 1205 - Variant is maternally inherited. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2023	This sequence change creates a premature translational stop signal (p.Trp2994*) in the USH2A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518041, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Usher syndrome or retinitis pigmentosa (PMID: 19881469, 28041643). ClinVar contains an entry for this variant (Variation ID: 48611). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2024	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 28041643, 28559085, 31266775, 32037395, 35266249, 31964843, 19881469, 25649381, 34906470, 35457016, 37466950) -

Usher syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 25, 2019

Variant summary: USH2A c.8981G>A (p.Trp2994X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 1.6e-05 in 251094 control chromosomes (gnomAD). c.8981G>A has been reported in the literature in individuals affected with Usher syndrome and retinitis pigmentosa (e.g. Carss_2017, Stone_2017, Yan_2009). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant twice as pathogenic and once as likely pathogenic. 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

Counsyl

Apr 12, 2017

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 02, 2010

The Trp2994X variant in USH2A has been reported in 2 probands with Usher syndrom e (Yan 2009). In addition, this variant leads to a premature stop codon at posit ion 2994 and therefore, is predicted to lead to a truncated or absent protein. I n summary, this variant meets our criteria to be classified as pathogenic (http: //pcpgm.partners.org/LMM). -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 18, 2019

- -

Retinitis pigmentosa

Pathogenic:1

Pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Benign

0.96

Eigen

Benign

-0.078

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.015

MutationTaster

Benign

1.0

A;A

Vest4

0.80

GERP RS

-5.0

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