NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Dec 12, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001051381.42

Allele description [Variation Report for NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr)]

NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr)

Genes:

LOC122152296:Sharpr-MPRA regulatory region 8762 [Gene]
USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.2332G>T (p.Asp778Tyr)

HGVS:

NC_000001.11:g.216247062C>A
NG_009497.2:g.181387G>T
NM_007123.6:c.2332G>T
NM_206933.4:c.2332G>TMANE SELECT
NP_009054.6:p.Asp778Tyr
NP_996816.3:p.Asp778Tyr
NC_000001.10:g.216420404C>A
NG_009497.1:g.181335G>T
NM_206933.2:c.2332G>T

Protein change:

D778Y

Links:

dbSNP: rs142898216

NCBI 1000 Genomes Browser:

rs142898216

Molecular consequence:

NM_007123.6:c.2332G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.2332G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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
SCV001215533	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 17085681, 25649381, 26969326, 28492532
SCV001248857	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (May 1, 2017)	germline	clinical testing	Citation Link,
SCV001802507	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Apr 6, 2021)	germline	clinical testing	Citation Link,
SCV002048766	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Apr 13, 2021)	germline	clinical testing	Citation Link

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

Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II.

Aller E, Jaijo T, Beneyto M, Nájera C, Oltra S, Ayuso C, Baiget M, Carballo M, Antiñolo G, Valverde D, Moreno F, Vilela C, Collado D, Pérez-Garrigues H, Navea A, Millán JM.

J Med Genet. 2006 Nov;43(11):e55.

PubMed [citation]

PMID:: 17085681
PMCID:: PMC2563181

A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants.

Lenassi E, Vincent A, Li Z, Saihan Z, Coffey AJ, Steele-Stallard HB, Moore AT, Steel KP, Luxon LM, Héon E, Bitner-Glindzicz M, Webster AR.

Eur J Hum Genet. 2015 Oct;23(10):1318-27. doi: 10.1038/ejhg.2014.283. Epub 2015 Feb 4.

PubMed [citation]

PMID:: 25649381
PMCID:: PMC4592079

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001215533.5

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

Description

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 778 of the USH2A protein (p.Asp778Tyr). This variant is present in population databases (rs142898216, gnomAD 0.05%). This missense change has been observed in individual(s) with Usher syndrome or non-syndromic retinal disease (PMID: 17085681, 25649381, 26969326; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 178583). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt USH2A protein function with a positive predictive value of 95%. For these reasons, this variant has been 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 CeGaT Center for Human Genetics Tuebingen, SCV001248857.26

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

#	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 GeneDx, SCV001802507.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31904091, 31736247, 17085681, 26969326, 32637036, 25649381)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048766.1

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

Description

The USH2A c.2332G>T; p.Asp778Tyr variant (rs142898216; ClinVar Variation ID: 178583) has been previously observed in patients with clinical features of Usher syndrome (US) or retinitis pigmentosa (RP). One patient with US found to be homozygous for this variant, while one US and one RP patient were found to carry this variant in a presumed transheterozygous configuration with other established pathogenic variants in USH2A (Aller 2006, Lenassi 2015, Sloan-Heggen 2016). This variants is rare in the general population, though it is found at higher frequencies is African Americans in in the Genome Aggregation Database (0.056% MAF; 14 out of 24,968 chromosomes, including 1 homozygous individual). The aspartic acid at codon 778 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.598). Based on the available information, the clinical significance of this variant is uncertain. References: Aller et al. Identification of 14 novel mutations in the long isoform of USH2A in Spanish patients with Usher syndrome type II. J Med Genet. 2006 Nov;43(11):e55. PMID: 17085681 Lenassi et al. A detailed clinical and molecular survey of subjects with nonsyndromic USH2A retinopathy reveals an allelic hierarchy of disease-causing variants. Eur J Hum Genet. 2015 Oct;23(10):1318-27. PMID: 25649381 Sloan-Heggen et al. Comprehensive genetic testing in the clinical evaluation of 1119 patients with hearing loss. Hum Genet. 2016 Apr;135(4):441-450. PMID: 26969326

#	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 3, 2024

ClinVar

Relating variation to medicine