NM_206933.4(USH2A):c.5776+1G>A AND Usher syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 15, 2023
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:: RCV001375185.5

Allele description [Variation Report for NM_206933.4(USH2A):c.5776+1G>A]

NM_206933.4(USH2A):c.5776+1G>A

Genes:

USH2A-AS2:USH2A antisense RNA 2 [Gene - HGNC]
USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.5776+1G>A

Other names:

p.p.(=)

HGVS:

NC_000001.11:g.216073096C>T
NG_009497.2:g.355353G>A
NM_206933.4:c.5776+1G>AMANE SELECT
NC_000001.10:g.216246438C>T
NM_206933.2:c.5776+1G>A
NM_206933.3:c.5776+1G>A

Links:

dbSNP: rs876657731

NCBI 1000 Genomes Browser:

rs876657731

Molecular consequence:

NM_206933.4:c.5776+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001571791	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	criteria provided, single submitter (ClinGen HL ACMG Specifications v1)	Pathogenic (Apr 12, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18273898, 30311386
SCV004241187	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 15, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23591405, 30459346 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001571791

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

criteria provided, single submitter

(ClinGen HL ACMG Specifications v1)

Pathogenic
(Apr 12, 2021)

germline

clinical testing

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

SCV004241187

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 15, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II.

Dreyer B, Brox V, Tranebjaerg L, Rosenberg T, Sadeghi AM, Möller C, Nilssen O.

Hum Mutat. 2008 Mar;29(3):451. doi: 10.1002/humu.9524.

PubMed [citation]

PMID:: 18273898

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss.

Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN; et al.

Hum Mutat. 2018 Nov;39(11):1593-1613. doi: 10.1002/humu.23630.

PubMed [citation]

PMID:: 30311386
PMCID:: PMC6188673

See all PubMed Citations (4)

Details of each submission

From Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center, SCV001571791.2

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

Description

PVS1_Strong, PS1_Strong, PM2_Moderate, PM3_Supporting

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004241187.1

#	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.5776+1G>A 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 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, showing the variant causes exon skipping resulting in a shortened mRNA product in a minigene assay (Fuster-Garcia_2018). The variant allele was found at a frequency of 1.2e-05 in 250072 control chromosomes. c.5776+1G>A has been reported in the literature in multiple individuals affected with Usher Syndrome, including as a homozygous phenotype (e.g. Fuster-Garcia_2018, Glockle_2014). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 30459346, 23591405). 16 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. 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 24, 2024

ClinVar

Relating variation to medicine