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

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 9, 2018
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV000710341.11

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]

Condition(s)

Name:: Usher syndrome
Synonyms:: Usher Syndromes; Usher's syndrome
Identifiers:: MONDO: MONDO:0019501; MeSH: D052245; MedGen: C0271097; Orphanet: 886; OMIM: PS276900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000840538	ClinGen Hearing Loss Variant Curation Expert Panel	reviewed by expert panel (ClinGen HL ACMG Specifications v1)	Pathogenic (Oct 9, 2018)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 19023448, 25133613, 26338283, 24853665, 25356976, 19737284 Citation Link,
SCV005184824	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (May 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32188678, 19023448 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000840538

ClinGen Hearing Loss Variant Curation Expert Panel

reviewed by expert panel

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Oct 9, 2018)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV005184824

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(May 30, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

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

Comprehensive molecular diagnosis of 67 Chinese Usher syndrome probands: high rate of ethnicity specific mutations in Chinese USH patients.

Jiang L, Liang X, Li Y, Wang J, Zaneveld JE, Wang H, Xu S, Wang K, Wang B, Chen R, Sui R.

Orphanet J Rare Dis. 2015 Sep 4;10:110. doi: 10.1186/s13023-015-0329-3.

PubMed [citation]

PMID:: 26338283
PMCID:: PMC4559966

See all PubMed Citations (7)

Details of each submission

From ClinGen Hearing Loss Variant Curation Expert Panel, SCV000840538.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (6)

Description

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.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005184824.1

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

Description

Variant summary: USH2A c.8559-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 251134 control chromosomes (gnomAD). c.8559-2A>G has been reported in the literature in multiple individuals affected with Usher Syndrome (Dai_2008, Gao_2021). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19023448, 32188678). ClinVar contains an entry for this variant (Variation ID: 48604). Based on the evidence outlined above, the variant was 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

Last Updated: Nov 10, 2024

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