NM_206933.4(USH2A):c.8559-2A>G AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 2, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000592589.24

Allele description [Variation Report for NM_206933.4(USH2A):c.8559-2A>G]

NM_206933.4(USH2A):c.8559-2A>G

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.8559-2A>G

HGVS:

NC_000001.11:g.215877882T>C
NG_009497.2:g.550567A>G
NM_206933.4:c.8559-2A>GMANE SELECT
NC_000001.10:g.216051224T>C
NM_206933.2:c.8559-2A>G
NM_206933.3:c.8559-2A>G
c.8559-2A>G

Links:

dbSNP: rs397518039

NCBI 1000 Genomes Browser:

rs397518039

Molecular consequence:

NM_206933.4:c.8559-2A>G - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000700946	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (Jan 19, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19023448, 25133613, 25356976 Citation Link,
SCV000938861	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 2, 2024)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 16199547, 10729113, 10909849, 20507924, 25649381, 19023448, 19737284, 28492532
SCV001762245	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 17, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003826086	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005201214	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 27, 2023)	germline	clinical testing	Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Targeted next-generation sequencing reveals novel USH2A mutations associated with diverse disease phenotypes: implications for clinical and molecular diagnosis.

Chen X, Sheng X, Liu X, Li H, Liu Y, Rong W, Ha S, Liu W, Kang X, Zhao K, Zhao C.

PLoS One. 2014;9(8):e105439. doi: 10.1371/journal.pone.0105439.

PubMed [citation]

PMID:: 25133613
PMCID:: PMC4136877

Genotype-phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing.

Huang XF, Huang F, Wu KC, Wu J, Chen J, Pang CP, Lu F, Qu J, Jin ZB.

Genet Med. 2015 Apr;17(4):271-8. doi: 10.1038/gim.2014.138. Epub 2014 Nov 6.

PubMed [citation]

PMID:: 25356976

See all PubMed Citations (11)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000700946.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (3)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000938861.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001762245.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003826086.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV005201214.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Canonical splice site variant expected to result in aberrant splicing, and published functional studies demonstrate skipping of exon 43 (PMID: 20596040); Reported as pathogenic by the ClinGen Hearing Loss Variant Curation Expert Panel (ClinVar SCV000840538.3; ClinVar); This variant is associated with the following publications: (PMID: 25356976, 21593743, 25252889, 28512305, 25078356, 34416374, 33629268, 30311386, 32531858, 35062939, 25133613, 25525159, 19023448, 26252086, 24853665, 19737284, 28968992, 26496393, 25558175, 29899460, 30029497, 29625443, 31872526, 31960602, 32093671, 31904091, 32100970, 31541171, 32188678, 33105608, 33124170, 34376197, 32675063, 32893482, 33090715, 33946315, 33691693, 34721897, 35870892, 35152177, 35052368, 34824372, 20596040, 26338283)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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