NM_206933.4(USH2A):c.908G>A (p.Arg303His) AND not provided

Clinical significance:Pathogenic (Last evaluated: Jul 1, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000276147.8

Allele description [Variation Report for NM_206933.4(USH2A):c.908G>A (p.Arg303His)]

NM_206933.4(USH2A):c.908G>A (p.Arg303His)

Gene:
USH2A:usherin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q41
Genomic location:
Preferred name:
NM_206933.4(USH2A):c.908G>A (p.Arg303His)
HGVS:
  • NC_000001.11:g.216325540C>T
  • NG_009497.1:g.102857G>A
  • NG_009497.2:g.102909G>A
  • NM_007123.6:c.908G>A
  • NM_206933.4:c.908G>AMANE SELECT
  • NP_009054.6:p.Arg303His
  • NP_996816.3:p.Arg303His
  • NC_000001.10:g.216498882C>T
  • NM_206933.2:c.908G>A
Protein change:
R303H
Links:
dbSNP: rs371777049
NCBI 1000 Genomes Browser:
rs371777049
Molecular consequence:
  • NM_007123.6:c.908G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_206933.4:c.908G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
7

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000337027EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Pathogenic
(Dec 1, 2015)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV001224324Invitaecriteria provided, single submitter
Pathogenic
(Oct 20, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001250065CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Pathogenic
(Jul 1, 2021)
germlineclinical testing

Citation Link,

SCV001766817GeneDxcriteria provided, single submitter
Pathogenic
(Oct 30, 2020)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot providednot providednot providedclinical testing
not providedgermlineyes6not providednot providednot providednot providedclinical testing

Citations

PubMed

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis.

Bonnet C, Grati M, Marlin S, Levilliers J, Hardelin JP, Parodi M, Niasme-Grare M, Zelenika D, Délépine M, Feldmann D, Jonard L, El-Amraoui A, Weil D, Delobel B, Vincent C, Dollfus H, Eliot MM, David A, Calais C, Vigneron J, Montaut-Verient B, Bonneau D, et al.

Orphanet J Rare Dis. 2011 May 11;6:21. doi: 10.1186/1750-1172-6-21.

PubMed [citation]
PMID:
21569298
PMCID:
PMC3125325

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations.

Garcia-Garcia G, Aparisi MJ, Jaijo T, Rodrigo R, Leon AM, Avila-Fernandez A, Blanco-Kelly F, Bernal S, Navarro R, Diaz-Llopis M, Baiget M, Ayuso C, Millan JM, Aller E.

Orphanet J Rare Dis. 2011 Oct 17;6:65. doi: 10.1186/1750-1172-6-65.

PubMed [citation]
PMID:
22004887
PMCID:
PMC3207874
See all PubMed Citations (8)

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, SCV000337027.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided1not providednot providednot provided

From Invitae, SCV001224324.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine with histidine at codon 303 of the USH2A protein (p.Arg303His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371777049, ExAC 0.008%). This variant has been observed in individual(s) with Usher syndrome and retinitis pigmentosa (PMID: 19881469, 28157192, 25342620). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 284411). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0. The histidine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg303 amino acid residue in USH2A. Other variant(s) that disrupt this residue have been observed in individuals with USH2A-related conditions (PMID:28157192, 14970843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001250065.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided6not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided6not providednot providednot provided

From GeneDx, SCV001766817.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 24944099, 25342620, 22004887, 21569298, 28157192, 31766479, 30872814, 19881469)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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