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NM_206933.4(USH2A):c.9110G>A (p.Arg3037His) AND not specified

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Dec 8, 2022
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:
RCV000218151.7

Allele description [Variation Report for NM_206933.4(USH2A):c.9110G>A (p.Arg3037His)]

NM_206933.4(USH2A):c.9110G>A (p.Arg3037His)

Gene:
USH2A:usherin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q41
Genomic location:
Preferred name:
NM_206933.4(USH2A):c.9110G>A (p.Arg3037His)
HGVS:
  • NC_000001.11:g.215844442C>T
  • NG_009497.2:g.584007G>A
  • NM_206933.4:c.9110G>AMANE SELECT
  • NP_996816.3:p.Arg3037His
  • NC_000001.10:g.216017784C>T
  • NG_009497.1:g.583955G>A
  • NM_206933.2:c.9110G>A
  • NM_206933.3:c.9110G>A
Protein change:
R3037H
Links:
dbSNP: rs533700989
NCBI 1000 Genomes Browser:
rs533700989
Molecular consequence:
  • NM_206933.4:c.9110G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000269952Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)
Benign
(Feb 20, 2015)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002819376Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Uncertain significance
(Dec 8, 2022)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided33not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000269952.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testing PubMed (1)

Description

p.Arg3037His in exon 46 of USH2A: This variant is not expected to have clinical significance because it has been identified in 0.7% (109/16492) of South Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs533700989), and due to a lack of conservation across species, incl uding mammals. Of note, 10 have a histidine (His) at this position despite high nearby amino acid conservation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided3not provided3not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819376.1

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

Description

Variant summary: USH2A c.9110G>A (p.Arg3037His) results in a non-conservative amino acid change located in the Fibronectin type III (IPR003961) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00079 in 249924 control chromosomes, predominantly at a frequency of 0.006 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in USH2A causing Usher Syndrome (0.00079 vs 0.011), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.9110G>A in individuals affected with Usher Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, with one laboratory classifying it as uncertain significance and four as benign or likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.

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

Last Updated: Nov 3, 2024