NM_206933.4(USH2A):c.2299del (p.Glu767fs) AND Usher syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jul 24, 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:: RCV000504641.6

Allele description [Variation Report for NM_206933.4(USH2A):c.2299del (p.Glu767fs)]

NM_206933.4(USH2A):c.2299del (p.Glu767fs)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.2299del (p.Glu767fs)

Other names:

p.Glu767SerfsX21; NP_996816.3:p.(Glu767SerfsTer21)

HGVS:

NC_000001.11:g.216247095del
NG_009497.2:g.181354del
NG_076570.1:g.469del
NM_007123.6:c.2299del
NM_206933.4:c.2299delMANE SELECT
NP_009054.5:p.Glu767fs
NP_009054.6:p.Glu767fs
NP_996816.3:p.Glu767fs
NC_000001.10:g.216420437del
NC_000001.10:g.216420437delC
NG_009497.1:g.181302del
NM_007123.5:c.2299del
NM_007123.5:c.2299del
NM_007123.5:c.2299delG
NM_206933.2:c.2299delG
NM_206933.3:c.2299del
NM_206933.3:c.2299delG
NM_206933.4:c.2299delGMANE SELECT
c.2299delG

Note:

NCBI staff reviewed the sequence information reported in PubMed 9624053 Fig. 2B to determine the location of this allele on the current reference sequence.

Protein change:

E767fs

Links:

OMIM: 608400.0001; dbSNP: rs80338903

NCBI 1000 Genomes Browser:

rs80338903

Molecular consequence:

NM_007123.6:c.2299del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_206933.4:c.2299del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000598800	NIHR Bioresource Rare Diseases, University of Cambridge	no assertion criteria provided	Pathogenic (Jan 1, 2015)	unknown	research	PubMed (2) [See all records that cite these PMIDs] 9624053, 28041643
SCV000926729	Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD	no assertion criteria provided	Pathogenic (Apr 1, 2018)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV001362171	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 25, 2019)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 14970843, 29953849, 24607488 Citation Link,
SCV004030341	Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 24, 2023)	germline	research	PubMed (2) [See all records that cite these PMIDs] 36909829, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research
European	unknown	yes	6	not provided	not provided	6	not provided	research
NA	unknown	yes	1	not provided	not provided	1	not provided	research

Citations

PubMed

Mutation of a gene encoding a protein with extracellular matrix motifs in Usher syndrome type IIa.

Eudy JD, Weston MD, Yao S, Hoover DM, Rehm HL, Ma-Edmonds M, Yan D, Ahmad I, Cheng JJ, Ayuso C, Cremers C, Davenport S, Moller C, Talmadge CB, Beisel KW, Tamayo M, Morton CC, Swaroop A, Kimberling WJ, Sumegi J.

Science. 1998 Jun 12;280(5370):1753-7.

PubMed [citation]

PMID:: 9624053

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

See all PubMed Citations (8)

Details of each submission

From NIHR Bioresource Rare Diseases, University of Cambridge, SCV000598800.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	European	1	not provided	not provided	research	PubMed (2)
2	European	1	not provided	not provided	research	PubMed (2)
3	European	1	not provided	not provided	research	PubMed (2)
4	European	1	not provided	not provided	research	PubMed (2)
5	European	1	not provided	not provided	research	PubMed (2)
6	European	1	not provided	not provided	research	PubMed (2)
7	NA	1	not provided	not provided	research	PubMed (2)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
2	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
3	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
4	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
5	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
6	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided
7	unknown	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet - VeluxRD, SCV000926729.2

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	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, SCV001362171.1

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

Description

Variant summary: USH2A c.2299delG (p.Glu767SerfsX21) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.00076 in 250832 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher syndrome (0.00076 vs 0.013), allowing no conclusion about variant significance. c.2299delG has been reported in the literature in multiple individuals affected with Usher syndrome. This variant appears to be a common USH2A mutation contributing to Usher Syndrome Type II (e.g. Aller_2004, Calzetti_2018 and Gene Reviews). Lenassi et al suggest that this change could disrupt an exonic splicing enhancer and create an exonic splicing silencer within exon 13 and therefore affect splicing of exons 12 and 13 of USH2A (Lenassi_2014). Nine ClinVar submitters (evaluation after 2014) cite this 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

From Ophthalmic Genetics Group, Institute of Molecular and Clinical Ophthalmology Basel, SCV004030341.1

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

Description

Clinical significance based on ACMG v2.0

#	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		1	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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