rs111033367

Positions:

chr1-216190279-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PP1_ModeratePM2PVS1PP4PM3

This summary comes from the ClinGen Evidence Repository: The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID:9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID:20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID:9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA252228/MONDO:0019501/005

Frequency

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

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

USH2A
NM_206933.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:13O:1

Conservation

PhyloP100: 7.84

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 15 ACMG points.

PVS1

PM2

PM3

PP1

PP4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
USH2A	NM_206933.4 linkuse as main transcript	c.4338_4339del	p.Cys1447GlnfsTer29	frameshift_variant	20/72	ENST00000307340.8
USH2A	NM_007123.6 linkuse as main transcript	c.4338_4339del	p.Cys1447GlnfsTer29	frameshift_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
USH2A	ENST00000307340.8 linkuse as main transcript	c.4338_4339del	p.Cys1447GlnfsTer29	frameshift_variant	20/72	1	NM_206933.4	P1	O75445-1
USH2A	ENST00000366942.3 linkuse as main transcript	c.4338_4339del	p.Cys1447GlnfsTer29	frameshift_variant	20/21	1			O75445-2
USH2A	ENST00000674083.1 linkuse as main transcript	c.4338_4339del	p.Cys1447GlnfsTer29	frameshift_variant	20/73				O75445-3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151840

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:

0.00000399

AC:

AN:

250692

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135502

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:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1460590

Hom.:

AF XY:

0.0000193

AC XY:

AN XY:

726642

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:

0.0000225

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151840

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

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

Bravo

AF:

0.00000756

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Retinitis pigmentosa 39

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 05, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Jan 11, 2017	- -
Pathogenic, criteria provided, single submitter	research	Ocular Genomics Institute, Massachusetts Eye and Ear	Apr 08, 2021	The USH2A c.4338_4339del 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, PM3, PP1-S, PP4. Based on this evidence we have classified this variant as Pathogenic. -

USH2A-related disorder

Pathogenic:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 05-24-2019 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely pathogenic, criteria provided, single submitter	research	UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	-	The USH2A c.4338_4339delCT (p.C1447Qfs) frameshift variant has been previously reported in multiple individuals with Usher syndrome, type IIA or nonsyndromic retinitis pigmentosa (PMID: 18641288; 15325563). -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The USH2A c.4338_4339delCT (p.Cys1447GlnfsTer29) variant results in a frameshift and is predicted to result in premature termination of the protein. The p.Cys1447GlnfsTer29 variant has been reported in six studies in which it is found in a total of 22 individuals with USH2A-related disorders, including in seven in a homozygous state, in two in a compound heterozygous state, and in 13 in a heterozygous state where a second variant was not found (Eudy et al. 1998; Weston et al. 2000; Seyedahmadi et al. 2004; Ebermann et al. 2009; Ebermann et al. 2010; Kimberling et al. 2010). The p.Cys1447GlnfsTer29 variant was absent from 493 controls but is reported at a frequency of 0.000008 in the European (non-Finnish) population of the Genome Aggregation Database. This is based on one allele only in a region of good sequence coverage so the variant is presumed rare. Based on the potential impact of frameshift variants and supporting evidence, the p.Cys1447GlnfsTer29 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:2

Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 25, 2018	The allele frequency of the p.Cys1447GlnfsX29 variant in the USH2A gene is 0.0009% (1/111250) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2 based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss (PM2). The p.Cys1447GlnfsX29 variant is predicted to cause a premature stop codon in biologically-relevant-exon 20 of 72 that leads to an absent protein in a gene in which loss-of-function is an established mechanism (PVS1). This variant has been detected as compound heterozygous with p.Cys759Phe or p.Glu767SerfsX21 in six Usher syndrome probands, and as homozygous in eight Usher syndrome probands (PM3_VeryStrong; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). The p.Cys1447GlnfsX29 variant in USH2A has been reported to segregate with hearing loss in at least 2 family members (PP1_Moderate; PMID: 20440071, 9624053). At least one patient with a variant in this gene displayed features of mild to severe hearing loss and retinitis pigmentosa (PP4; PMID: 9624053, 15325563, 18641288, 18665195, 20440071). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome based on the ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: PM2, PVS1, PM3_VeryStrong, PP1_Moderate, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 15, 2021	The p.Cys1447GlnfsX29 variant in USH2A has been reported in at least 14 individuals with Usher syndrome and 21 individuals with autosomal recessive retinitis pigmentosa, 17 of whom were homozygous or compound heterozygous (Eudy 1998 PMID: 9624053, Seyedahmedi 2004 PMID: 15325563, Sandberg 2008 PMID: 18641288, Ebermann 2009 PMID: 18665195, Kimberling 2010 PMID: 20613545). This variant segregated with disease in 2 individuals from 2 families (Eudy 1998 PMID: 9624053, Ebermann 2010 PMID: 20440071). This variant has also been identified in 0.0008% (1/113304) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is low enough to be consistent with a recessive carrier frequency. This variant was classified as Pathogenic on Feb 27, 2019 by the ClinGen-approved Hearing Loss Variant Curation expert panel (Variation ID 2353). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1447 and leads to a premature stop codon 29 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, the p.Cys1447GlnfsX29 variant meets criteria to be classified as pathogenic for autosomal recessive Usher syndrome. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PP1_Moderate, PM2_Supporting. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2022	Frameshift 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: 10729113, 15325563, 24944099, 18665195, 30311386, 9624053, 20440071, 25425308, 21234346, 20613545, 18641288, 31047384, 32853555, 34313030, 34039936) -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change creates a premature translational stop signal (p.Cys1447Glnfs*29) 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 (rs111033367, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with Usher syndrome (PMID: 9624053, 20440071). ClinVar contains an entry for this variant (Variation ID: 2353). For these reasons, this variant has been classified as Pathogenic. -

Usher syndrome type 2A

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2010	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 18, 2022

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Nov 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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