NM_206933.4(USH2A):c.12575G>A (p.Arg4192His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (6 submissions)
Last evaluated:: Feb 15, 2024
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:: RCV000480057.46

Allele description [Variation Report for NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)]

NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.12575G>A (p.Arg4192His)

HGVS:

NC_000001.11:g.215675336C>T
NG_009497.2:g.753113G>A
NM_206933.3:c.12575G>A
NM_206933.4:c.12575G>AMANE SELECT
NP_996816.3:p.Arg4192His
NC_000001.10:g.215848678C>T
NG_009497.1:g.753061G>A
NM_206933.2:c.12575G>A
NM_206933.3(USH2A):c.12575G>A
NM_206933.4:c.12575G>A
O75445:p.Arg4192His

Protein change:

R4192H

Links:

UniProtKB: O75445#VAR_068358; dbSNP: rs199605265

NCBI 1000 Genomes Browser:

rs199605265

Molecular consequence:

NM_206933.4:c.12575G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Repurposed nuclear speckle and mitosis components induce CTCF clustering to sust...
Repurposed nuclear speckle and mitosis components induce CTCF clustering to sustain the senescence splicing program [eCLIP]
Repurposed nuclear speckle and mitosis components induce CTCF clustering to sustain the senescence splicing program [eCLIP]

BioProject
DFFA DNA fragmentation factor subunit alpha [Homo sapiens]
DFFA DNA fragmentation factor subunit alpha [Homo sapiens]
Gene ID:1676

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000331629	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Pathogenic (May 7, 2015)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20507924, 21151602, 22135276, 22334370, 23591405, 23991284, 25649381 Citation Link,
SCV000565653	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Feb 15, 2024)	germline	clinical testing	Citation Link,
SCV001057184	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305, 28492532
SCV001246243	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Uncertain significance (Jul 1, 2019)	germline	clinical testing	Citation Link,
SCV001447609	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003828074	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jun 18, 2019)	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	2	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	3	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.

McGee TL, Seyedahmadi BJ, Sweeney MO, Dryja TP, Berson EL.

J Med Genet. 2010 Jul;47(7):499-506. doi: 10.1136/jmg.2009.075143. Epub 2010 May 27.

PubMed [citation]

PMID:: 20507924
PMCID:: PMC3070405

Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies.

Glöckle N, Kohl S, Mohr J, Scheurenbrand T, Sprecher A, Weisschuh N, Bernd A, Rudolph G, Schubach M, Poloschek C, Zrenner E, Biskup S, Berger W, Wissinger B, Neidhardt J.

Eur J Hum Genet. 2014 Jan;22(1):99-104. doi: 10.1038/ejhg.2013.72. Epub 2013 Apr 17.

PubMed [citation]

PMID:: 23591405
PMCID:: PMC3865404

See all PubMed Citations (12)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000331629.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	PubMed (7)

#	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		3	not provided	not provided	not provided

From GeneDx, SCV000565653.8

#	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 supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 32637036, 25649381, 23591405, 26427457, 28131284, 26880948, 28559085, 21151602, 22334370, 27596865, 28118666, 30217765, 32326409, 31980526, 32036094, 32581362, 26806561, 25412400, 28041643, 26927203, 29276052, 31049658, 31736247, 32269941, 31456290, 28805479, 27160483, 20507924, 22135276, 34327195, 32675063, 28894305, 33576794, 32037395, 23991284, 34961661, 34781295, 35266249)

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001057184.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 4192 of the USH2A protein (p.Arg4192His). This variant is present in population databases (rs199605265, gnomAD 0.9%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with mild or late onset deafness and/or nonsyndromic retinal disease (PMID: 21151602, 22135276, 22334370, 23991284, 25649381, 28118666, 28559085, 28894305; 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: 166434). 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 not expected to disrupt USH2A protein function with a negative 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, SCV001246243.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447609.1

#	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	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003828074.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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