rs786200928

Variant names:

• chr1-215891198-T-C
• rs786200928
• NM_206933.4:c.7595-2144A>G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_206933.4(USH2A):​c.7595-2144A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000591 in 152,338 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 Likely pathogenic (★★).

• Frequency: Genomes: 𝑓 0.000059 (0 hom., cov: 32)
• Consequence: USH2A NM_206933.4 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:26 O:1
• Conservation: PhyloP100: 1.94

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]

ENSG00000229242 (HGNC:):

ACMG classification

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 1-215891198-T-C is Pathogenic according to our data. Variant chr1-215891198-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-215891198-T-C is described in Lovd as [Pathogenic]. Variant chr1-215891198-T-C is described in Lovd as [Pathogenic]. Variant chr1-215891198-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
USH2A	NM_206933.4	c.7595-2144A>G		intron_variant	Intron 40 of 71	ENST00000307340.8	NP_996816.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
USH2A	ENST00000307340.8	c.7595-2144A>G		intron_variant	Intron 40 of 71	1	NM_206933.4	ENSP00000305941.3
USH2A	ENST00000674083.1	c.7595-2144A>G		intron_variant	Intron 40 of 72			ENSP00000501296.1
ENSG00000229242	ENST00000414995.1	n.60+4557T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74488

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000680

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:26 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 07, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed with a second USH2A variant in multiple individuals with Usher syndrome in the published literature, however, the phase of these variants is unknown (Sodi et al., 2018; Khalaileh et al., 2018; Steele-Stallard et al., 2013); Non-canonical splice site variant demonstrated to result in loss-of-function; functional studies demonstrated an insertion of 152 bp at the junction of exons 40 and 41, leading to an out-of-frame protein with premature stop codon in exon 41 (designated p.K2532TfsX56) (Vache et al., 2012; Steele-Stallard et al., 2013); This variant is associated with the following publications: (PMID: 25404053, 33576794, 31980526, 31456290, 32581362, 31231422, 30718709, 26629787, 23924366, 30281416, 27802265, 25649381, 25823529, 28041643, 22009552, 25352746, 29490346, 25558175, 27460420, 32037395) -

May 14, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 40 of the USH2A gene. It does not directly 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 (rs786200928, gnomAD 0.007%). This variant has been observed in individual(s) with Usher syndrome (PMID: 22009552, 23924366). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30722). Studies have shown that this variant results in an insertion of 152bp at the junction of exons 40 and 41, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 22009552). For these reasons, this variant has been classified as Pathogenic. -

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2A Pathogenic:4

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

-

Genomics England Pilot Project, Genomics England

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome Pathogenic:3

Oct 30, 2020

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: USH2A c.7595-2144A>G is reported in the literature to induce activation of a pseudoexon, predicted to result in a frameshift of the protein (e.g. Vache_2011). Several computational tools predict a significant impact on normal splicing: Four predict that the variant creates a new 5' donor site. The variant allele was found at a frequency of 6.4e-05 in 31406 control chromosomes. c.7595-2144A>G has been reported in the literature in multiple individuals affected with Usher Syndrome, including evidence for cosegregation with disease in several families (e.g. Vache_2011, Steele-Stallard_2013). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence that this variant activates a pseudoexon, resulting in aberrant splicing (e.g. Vache_2011). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Retinitis pigmentosa 39 Pathogenic:3

Mar 19, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 08, 2021

Ocular Genomics Institute, Massachusetts Eye and Ear

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The USH2A c.7595-2144A>G 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: PM2, PM3, PP1, PP3. Based on this evidence we have classified this variant as Likely Pathogenic. -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

USH2A-related disorder Pathogenic:2 Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 06-28-2019 by Lab or GTR ID 500188. 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. -

Nov 07, 2022

Variantyx, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a non-canonical splice variant in the USH2A gene (OMIM 608400). Pathogenic variants in this gene have been associated with autosomal recessive USH2A-related disorders. This variant causes a splicing defect that results in retention of a 152-bp intronic segment at the junction of exons 40 and 41 (PMID: 22009552). This event introduces a premature stop codon and results in loss of function, which is a known disease mechanism for USH2A (PMID: 20507924) (PVS1). This variant has been observed in the homozygous or compound heterozygous state in several affected individuals, including evidence of segregation with disease in at least two families (PMID: 22009552, 23924366) (PP1_Moderate). This variant has a 0.01928% maximum allele frequency in non-founder control populations (https://gnomad.broadinstitute.org/), which is lower than expected for the prevalence of USH2A-related disease (PM2_Supporting). Based on current evidence, this variant is classified as pathogenic for autosomal recessive USH2A-related disorders. -

Aug 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The USH2A c.7595-2144A>G variant is predicted to interfere with splicing. This variant is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). This variant has previously been reported to be a common deep intronic variant causative for Usher syndrome type 2 (Aparisi et al. 2014. PubMed ID: 25404053; Liquori et al. 2016. PubMed ID: 26629787; Vaché et al. 2012. PubMed ID: 22009552; Lin et al. 2024. PubMed ID: 38219857). RNA analysis of nasal cells from one affected individual confirmed that this variant creates a pseudoexon (Vaché et al. 2012. PubMed ID: 22009552). This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Usher syndrome type 2A;C3151138:Retinitis pigmentosa 39 Pathogenic:2

Mar 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Pathogenic:2

Jan 01, 2021

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2019

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 2 Pathogenic:1

Jun 23, 2019

Sharon lab, Hadassah-Hebrew University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Rare genetic deafness Pathogenic:1

Nov 07, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

7595-2144A>G variant in USH2A has been reported in 9 individuals with USH2A in compound heterozygous state with another pathogenic USH2A allele, of which 6 were confirmed to occur in trans, segregated in 6 affected relatives and absent from 518 control chromosomes (Vache 2012). RNA samples from these patients showed abnormal splicing predicted to lead to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon segregation studies, low frequency in the general population, and observed deleterious impact on splicing. -

Retinitis pigmentosa Pathogenic:1

Apr 01, 2018

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	29
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.69		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786200928; hg19: chr1-216064540;