VCV000048604.30 - ClinVar - NCBI (2024)

Method: curation

(Autosomal recessive inheritance)

Affected status: unknown

Allele origin: germline

FDARecognizedDatabase
Accession: SCV000840538.4
First in ClinVar: Oct 21, 2018
Last updated: Dec 11, 2022

Publications:

PubMed (6)

PubMed: 19023448‚ 25133613‚ 26338283‚ 24853665‚ 25356976‚ 19737284

Other databases

https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/fe785bf9-af38-456e-83ed-6717335dbde4

Comment:

The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant … (more)

The c.8559-2A>G has been detected in >4 patients with Usher syndrome who were compound heterozygous for the this variant in trans with a truncating variant (PM3_VS; PMID: 25356976, 19737284, 26338283, 19023448). Segregation data was also available for two reported families with Usher syndrome. In one family, the variant was identified in trans with a frameshift variant in two affected siblings, and four unaffected siblings were either heterozygous for a single variant or wild-type for both variants. In the second family, an unaffected sibling was heterozygous for a single variant (PP1_Strong, PMID: 19023448). RT-PCR analysis of cells from a patient carrying the variant revealed that the variant causes skipping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (PM4, PMID: 20596040) The allele frequency of the c.8559-2A>G variant in the USH2A gene is 0.046% (8/17232) of East Asian chromosomes by the Genome Aggregation Database ( http://gnomad.broadinstitute.org), which is a low enough frequency to award PM2_supporting based on the thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive hearing loss and Usher syndrome (PM2_Supporting). Several patients reported to harbor this variant displayed clinical features of Usher syndrome (PP4; PMID: 25356976, 19737284, 26338283, 19023448). 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: PM4, PM3_VS, PP1_S, PP4, PM2_P. (less)

Method: clinical testing

Affected status: unknown

Allele origin: unknown

Accession: SCV000893286.2
First in ClinVar: Mar 31, 2019
Last updated: Dec 31, 2022

Publications:

PubMed (1)

PubMed: 25741868

pmc: 4544753 pmc: 4544753

DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30

Method: clinical testing

Affected status: unknown

Allele origin: germline

Accession: SCV003826086.2
First in ClinVar: Mar 04, 2023
Last updated: Feb 04, 2024

Method: clinical testing

Affected status: not provided

Allele origin: germline

Accession: SCV000065626.6
First in ClinVar: May 03, 2013
Last updated: Aug 26, 2019

Publications:

PubMed (3)

PubMed: 19023448‚ 19737284‚ 20596040

See Also

Mutation screening of the USH2A gene in retinitis pigmentosa and USHER patients in a Han Chinese populationMutation screening of the USH2A gene reveals two novel pathogenic variants in Chinese patients causing simplex usher syndrome 2

Comment:

The 8559-2A>G variant in USH2A has been reported in 6 Asian individuals with Ush er type 2 and was absent in 470 Asian control chromosomes … (more)

The 8559-2A>G variant in USH2A has been reported in 6 Asian individuals with Ush er type 2 and was absent in 470 Asian control chromosomes (Dai 2008, Nakanishi 2 009). All of these probands were compound heterozygous. This variant is predicte d to cause abnormal splicing because the nucleotide substitution occurs in the i nvariant region of the splice consensus sequence. Furthermore, RT-PCR analysis o f cells from a patient carrying the variant revealed that the variant causes ski pping of exon 43, resulting in a 41 amino acid deletion of the USH2A protein (Na kanishi 2010). In summary, this variant meets our criteria to be classified as p athogenic. (less)

Method: clinical testing

Affected status: unknown

Allele origin: unknown

Accession: SCV004208226.2
First in ClinVar: Dec 30, 2023
Last updated: Jun 17, 2024

Method: clinical testing

Affected status: unknown

Allele origin: germline

Accession: SCV000700946.2
First in ClinVar: Apr 02, 2018
Last updated: Apr 02, 2018

Publications:

PubMed (3)

PubMed: 19023448‚ 25133613‚ 25356976

Other databases

http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=USH2A

Method: clinical testing

Affected status: yes

Allele origin: germline

Method: clinical testing

(Autosomal recessive inheritance)

Affected status: yes

Allele origin: germline

Accession: SCV001762245.1
First in ClinVar: Jul 30, 2021
Last updated: Jul 30, 2021

Method: clinical testing

Affected status: yes

Allele origin: germline

Accession: SCV002059155.1
First in ClinVar: Jan 15, 2022
Last updated: Jan 15, 2022

Publications:

PMID:19737284

PMID:19737284

PMID:19023448

PMID:19023448

PMID:25356976

PMID:25356976

PMID:26338283

PMID:26338283

Comment:

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are … (more)

Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000048604, 3billion dataset). The variant was co-segregated with Usher syndrome, type 2A in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 19023448, PP1_S). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000032, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 19737284, 26338283, 25356976, 19023448, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)

Method: clinical testing

Affected status: unknown

Allele origin: unknown

Accession: SCV002060359.2
First in ClinVar: Jan 15, 2022
Last updated: Nov 29, 2022

Publications:

PubMed (3)

PubMed: 25356976‚ 25324289‚ 20596040

Comment:

NM_206933.2(USH2A):c.8559-2A>G is a canonical splice site variant classified as pathogenic in the context of USH2A-related disorders. c.8559-2A>G has been observed in cases with relevant disease … (more)

NM_206933.2(USH2A):c.8559-2A>G is a canonical splice site variant classified as pathogenic in the context of USH2A-related disorders. c.8559-2A>G has been observed in cases with relevant disease (PMID: 25324289, 20596040, 25356976). Functional assessments of this variant are available in the literature (PMID: 20596040). c.8559-2A>G has been observed in population frequency databases (gnomAD: EAS 0.05%). In summary, NM_206933.2(USH2A):c.8559-2A>G is a canonical splice site variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)

Method: clinical testing

Affected status: unknown

Allele origin: germline

Accession: SCV000938861.6
First in ClinVar: Aug 14, 2019
Last updated: Feb 14, 2024

Publications:

PubMed (7)

PubMed: 16199547‚ 10729113‚ 10909849‚ 20507924‚ 25649381‚ 19023448‚ 19737284

Comment:

This sequence change affects an acceptor splice site in intron 42 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)

This sequence change affects an acceptor splice site in intron 42 of the USH2A gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in USH2A are known to be pathogenic (PMID: 10729113, 10909849, 20507924, 25649381). This variant is present in population databases (rs397518039, gnomAD 0.05%). Disruption of this splice site has been observed in individuals with Usher syndrome (PMID: 19023448, 19737284). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 48604). 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. (less)

Method: research

Affected status: yes

Allele origin: germline

Accession: SCV004707924.1
First in ClinVar: Mar 10, 2024
Last updated: Mar 10, 2024

Method: not provided

Affected status: not provided

Allele origin: not provided

Accession: SCV000172669.1
First in ClinVar: Aug 08, 2014
Last updated: Aug 08, 2014

Method: case-control

Affected status: yes

Allele origin: inherited

Accession: SCV000902401.1
First in ClinVar: May 13, 2019
Last updated: May 13, 2019

Method: clinical testing

Affected status: unknown

Allele origin: germline

Accession: SCV001458111.1
First in ClinVar: Jan 02, 2021
Last updated: Jan 02, 2021