NM_206933.4(USH2A):c.12574C>T (p.Arg4192Cys) AND not provided

Germline classification:: Pathogenic (7 submissions)
Last evaluated:: May 10, 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:: RCV000498898.50

Allele description [Variation Report for NM_206933.4(USH2A):c.12574C>T (p.Arg4192Cys)]

NM_206933.4(USH2A):c.12574C>T (p.Arg4192Cys)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.12574C>T (p.Arg4192Cys)

HGVS:

NC_000001.11:g.215675337G>A
NG_009497.2:g.753112C>T
NM_206933.4:c.12574C>TMANE SELECT
NP_996816.3:p.Arg4192Cys
NC_000001.10:g.215848679G>A
NG_009497.1:g.753060C>T
NM_206933.2:c.12574C>T
NM_206933.3(USH2A):c.12574C>T
p.Arg4192Cys

Protein change:

R4192C

Links:

dbSNP: rs750396156

NCBI 1000 Genomes Browser:

rs750396156

Molecular consequence:

NM_206933.4:c.12574C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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myoglobin, partial [Elachura formosa]
myoglobin, partial [Elachura formosa]
gi|602219799|gb|AHN92473.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000589528	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 10, 2024)	germline	clinical testing	Citation Link,
SCV001207227	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 23, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23940504, 27157150, 29912909, 32176120, 33576794, 28492532
SCV001246244	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link,
SCV001446632	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001921192	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing
SCV001954205	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	4	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis.

Corton M, Nishiguchi KM, Avila-Fernández A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, Ayuso C, Rivolta C.

PLoS One. 2013 Jun 14;8(6):e65574. doi: 10.1371/journal.pone.0065574. Print 2013. Erratum in: PLoS One. 2016 Mar 31;11(3):e0153121. doi: 10.1371/journal.pone.0153121.

PubMed [citation]

PMID:: 23940504
PMCID:: PMC3683009

Retinal Dystrophy in 6 Young Patients Who Presented with Intermediate Uveitis.

Hettinga YM, van Genderen MM, Wieringa W, Ossewaarde-van Norel J, de Boer JH.

Ophthalmology. 2016 Sep;123(9):2043-6. doi: 10.1016/j.ophtha.2016.03.046. Epub 2016 May 4. No abstract available.

PubMed [citation]

PMID:: 27157150

See all PubMed Citations (7)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000332810.4

#	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	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From GeneDx, SCV000589528.7

#	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 has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32531858, 34758253, 23940504, 24516651, 27157150, 24625443, 25649381, 28041643, 32176120, 32581362, 34426522, 33576794, 36011334, 34948090, 32637036, 34781295, 30190494, 28127548, 35266249, 36785559, 29912909, 27460420)

#	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, SCV001207227.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4192 of the USH2A protein (p.Arg4192Cys). This variant is present in population databases (rs750396156, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive retinitis pigmentosa (arRP) (PMID: 23940504, 27157150, 29912909, 32176120, 33576794). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 281818). 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 80%. 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, SCV001246244.26

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

Description

USH2A: PM3:Very Strong, PM2, PM5

#	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		4	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001446632.1

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001921192.1

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001954205.1

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000332810	Eurofins Ntd Llc (ga)	flagged submission Reason: Conflicts with expert reviewed submission without evidence to support different classification Notes: None (EGL Classification Definitions 2015)	Uncertain significance (Jul 10, 2015)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000332810

Eurofins Ntd Llc (ga)

flagged submission

Reason: Conflicts with expert reviewed submission without evidence to support different classification

Notes: None

(EGL Classification Definitions 2015)

Uncertain significance
(Jul 10, 2015)

germline

clinical testing

Citation Link

Last Updated: Oct 26, 2024

Relating variation to medicine