NM_206933.4(USH2A):c.12284G>A (p.Gly4095Asp) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 12, 2024
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:: RCV000435312.29

Allele description [Variation Report for NM_206933.4(USH2A):c.12284G>A (p.Gly4095Asp)]

NM_206933.4(USH2A):c.12284G>A (p.Gly4095Asp)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.12284G>A (p.Gly4095Asp)

HGVS:

NC_000001.11:g.215680159C>T
NG_009497.2:g.748290G>A
NM_206933.4:c.12284G>AMANE SELECT
NP_996816.2:p.Gly4095Asp
NP_996816.3:p.Gly4095Asp
NC_000001.10:g.215853501C>T
NG_009497.1:g.748238G>A
NM_206933.2:c.12284G>A
NM_206933.3:c.12284G>A

Protein change:

G4095D

Links:

dbSNP: rs759898765

NCBI 1000 Genomes Browser:

rs759898765

Molecular consequence:

NM_206933.4:c.12284G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000515237	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Feb 28, 2023)	germline	clinical testing	Citation Link,
SCV001246245	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2018)	germline	clinical testing	Citation Link,
SCV001374868	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 12, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25333064, 27460420, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000515237

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Feb 28, 2023)

germline

clinical testing

Citation Link,

SCV001246245

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Apr 1, 2018)

germline

clinical testing

Citation Link,

SCV001374868

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 12, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Screening for single nucleotide variants, small indels and exon deletions with a next-generation sequencing based gene panel approach for Usher syndrome.

Krawitz PM, Schiska D, Krüger U, Appelt S, Heinrich V, Parkhomchuk D, Timmermann B, Millan JM, Robinson PN, Mundlos S, Hecht J, Gross M.

Mol Genet Genomic Med. 2014 Sep;2(5):393-401. doi: 10.1002/mgg3.92. Epub 2014 Jun 15.

PubMed [citation]

PMID:: 25333064
PMCID:: PMC4190874

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 (3)

Details of each submission

From GeneDx, SCV000515237.5

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

Description

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 27460420, 25333064, 35266249, 32675063)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001246245.25

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001374868.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 4095 of the USH2A protein (p.Gly4095Asp). This variant is present in population databases (rs759898765, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Usher syndrome or retinitis pigmentosa (PMID: 25333064, 27460420; Invitae). ClinVar contains an entry for this variant (Variation ID: 378847). 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%. This variant disrupts the p.Gly4095 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID: 27460420), which suggests that this may be a clinically significant amino acid residue. 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

Last Updated: Oct 13, 2024

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