NM_206933.4(USH2A):c.1111_1112del (p.Ile371fs) AND Usher syndrome type 2A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Nov 4, 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:: RCV000588348.5

Allele description [Variation Report for NM_206933.4(USH2A):c.1111_1112del (p.Ile371fs)]

NM_206933.4(USH2A):c.1111_1112del (p.Ile371fs)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.1111_1112del (p.Ile371fs)

HGVS:

NC_000001.11:g.216325337_216325338del
NG_009497.2:g.103112_103113del
NM_007123.6:c.1111_1112del
NM_206933.4:c.1111_1112delMANE SELECT
NP_009054.6:p.Ile371fs
NP_996816.3:p.Ile371fs
NC_000001.10:g.216498678_216498679del
NC_000001.10:g.216498679_216498680del
NG_009497.1:g.103060_103061del
NM_206933.2:c.1111_1112del
NM_206933.2:c.1111_1112delAT
NM_206933.4:c.1111_1112delATMANE SELECT
p.Ile371PhefsTer3

Protein change:

I371fs

Links:

dbSNP: rs1366496013

NCBI 1000 Genomes Browser:

rs1366496013

Molecular consequence:

NM_007123.6:c.1111_1112del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_206933.4:c.1111_1112del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Usher syndrome type 2A
Synonyms:: USHER SYNDROME, TYPE IIA; RETINAL DISEASE IN USHER SYNDROME TYPE IIA, MODIFIER OF
Identifiers:: MONDO: MONDO:0010169; MedGen: C1848634; Orphanet: 231178; Orphanet: 886; OMIM: 276901

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000693911	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 25, 2017)	germline	research	PubMed (2) [See all records that cite these PMIDs] 16963483, 25741868
SCV002556437	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 23, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16963483, 18641288, 32176120, 25741868
SCV004182909	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000693911

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG)

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jun 25, 2017)

germline

research

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

SCV002556437

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 23, 2022)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004182909

Genome-Nilou Lab

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 4, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	1	not provided	not provided	not provided	clinical testing, research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Development of a genotyping microarray for Usher syndrome.

Cremers FP, Kimberling WJ, Külm M, de Brouwer AP, van Wijk E, te Brinke H, Cremers CW, Hoefsloot LH, Banfi S, Simonelli F, Fleischhauer JC, Berger W, Kelley PM, Haralambous E, Bitner-Glindzicz M, Webster AR, Saihan Z, De Baere E, Leroy BP, Silvestri G, McKay GJ, Koenekoop RK, et al.

J Med Genet. 2007 Feb;44(2):153-60. Epub 2006 Sep 8.

PubMed [citation]

PMID:: 16963483
PMCID:: PMC2598068

Disease course in patients with autosomal recessive retinitis pigmentosa due to the USH2A gene.

Sandberg MA, Rosner B, Weigel-DiFranco C, McGee TL, Dryja TP, Berson EL.

Invest Ophthalmol Vis Sci. 2008 Dec;49(12):5532-9. doi: 10.1167/iovs.08-2009. Epub 2008 Jul 18.

PubMed [citation]

PMID:: 18641288
PMCID:: PMC2588642

See all PubMed Citations (4)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard - Broad Institute Center for Mendelian Genomics (CMG), SCV000693911.1

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

Description

Reportedly 1 case with this variant in the supplement but that is not available at the time of review (broken link). In trans to a known pathogenic variant. In gnomAD, not found in exomes, once in genomes (1/30960 chromosomes). (PM2, PM3, PVS1).

#	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	1	not provided

From Genetics and Molecular Pathology, SA Pathology, SCV002556437.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The USH2A c.1111_1112del variant is classified as PATHOGENIC (PVS1, PM2, PS4_S) This variant is a deletion of two consecutive nucleotides in exon 6/72 of the USH2A gene, predicted to encode a frame shift of the mature mRNA with consequent premature termination of protein synthesis at codon 3 of the frame-shift, or 373 (USH2A:p.(Ile371PhefsTer3)) (PVS1). The variant has been identified in multiple unrelated individuals with Usher syndrome and non-syndromic Retinitis pigmentosa, and confirmed in trans with a second pathogenic variant in an individual with non-syndromic Retinitis pigmentosa (PMID:16963483, PMID:32176120, PMID:18641288). The variant is in dbSNP (rs1366496013) but it is rare in population databases (gnomAD: 1/152208, 0 homozygote) (PM2). This variant has been reported in ClinVar (VariationID: 495336) and HGMD (Accession: CD071406) as disease causing variant (PS4_S).

#	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 Genome-Nilou Lab, SCV004182909.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Dec 14, 2024

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