NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter) AND USH2A-related disorder

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 9, 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:: RCV001813732.5

Allele description [Variation Report for NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter)]

NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.11864G>A (p.Trp3955Ter)

HGVS:

NC_000001.11:g.215728232C>T
NG_009497.2:g.700217G>A
NM_206933.4:c.11864G>AMANE SELECT
NP_996816.3:p.Trp3955Ter
NC_000001.10:g.215901574C>T
NG_009497.1:g.700165G>A
NM_206933.2:c.11864G>A
NM_206933.3:c.11864G>A
c.11864G>A
p.Trp3955X

Protein change:

W3955*; TRP3955TER

Links:

OMIM: 608400.0007; dbSNP: rs111033364

NCBI 1000 Genomes Browser:

rs111033364

Molecular consequence:

NM_206933.4:c.11864G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: USH2A-related disorder
Synonyms:: USH2A-Related Disorders; USH2A-related condition
Identifiers:: MedGen: CN239332

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002061201	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 5, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 29293505, 27460420, 26927203, 25649381, 25575603, 25333064, 22135276, 21569298, 20507924, 25741868
SCV004718566	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 9, 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

SCV002061201

DASA

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 5, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004718566

PreventionGenetics, part of Exact Sciences

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Nov 9, 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	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

Diagnostic outcomes of exome sequencing in patients with syndromic or non-syndromic hearing loss.

Likar T, Hasanhodžić M, Teran N, Maver A, Peterlin B, Writzl K.

PLoS One. 2018;13(1):e0188578. doi: 10.1371/journal.pone.0188578.

PubMed [citation]

PMID:: 29293505
PMCID:: PMC5749682

An innovative strategy for the molecular diagnosis of Usher syndrome identifies causal biallelic mutations in 93% of European patients.

Bonnet C, Riahi Z, Chantot-Bastaraud S, Smagghe L, Letexier M, Marcaillou C, Lefèvre GM, Hardelin JP, El-Amraoui A, Singh-Estivalet A, Mohand-Saïd S, Kohl S, Kurtenbach A, Sliesoraityte I, Zobor D, Gherbi S, Testa F, Simonelli F, Banfi S, Fakin A, Glavač D, Jarc-Vidmar M, et al.

Eur J Hum Genet. 2016 Dec;24(12):1730-1738. doi: 10.1038/ejhg.2016.99. Epub 2016 Jul 27.

PubMed [citation]

PMID:: 27460420
PMCID:: PMC5117943

See all PubMed Citations (10)

Details of each submission

From DASA, SCV002061201.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (10)

Description

The c.11864G>A;p.(Trp3955*) variant creates a premature translational stop signal in the USH2A gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID:2357; PMID: 29293505; 27460420; 26927203; 25649381; 25575603; 25333064; 22135276; 21569298; 20507924) - PS4. The variant is present at low allele frequencies population databases (rs111033364 – gnomAD 0.01249%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Trp3955*) was detected in trans with a pathogenic variant (PMID: 29293505; 27460420; 25649381; 25575603; 25333064; 22135276; 21569298) - PM3_strong. The variant co-segregated with disease in multiple affected family members (PMID: 25575603) - PP1. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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

From PreventionGenetics, part of Exact Sciences, SCV004718566.1

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

Description

The USH2A c.11864G>A variant is predicted to result in premature protein termination (p.Trp3955*). This variant has been reported many times in individuals with Usher syndrome and is noted to be one of the most common pathogenic variants in USH2A, being detected in ~22% of a cohort of patients (see for examples Bonnet et al. 2016. PubMed ID: 27460420; Lenarduzzi et al. 2015. PubMed ID: 25575603; Table S4 in Stone et al. 2017. PubMed ID: 28559085). This variant is reported in 0.025% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-215901574-C-T). Nonsense variants in USH2A are expected to be pathogenic. Given the evidence, we interpret this variant 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: Jun 2, 2024

ClinVar

Relating variation to medicine