NM_206933.4(USH2A):c.12448A>G (p.Thr4150Ala) AND not specified

Clinical significance:Uncertain significance (Last evaluated: Nov 24, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001269243.1

Allele description [Variation Report for NM_206933.4(USH2A):c.12448A>G (p.Thr4150Ala)]

NM_206933.4(USH2A):c.12448A>G (p.Thr4150Ala)

Gene:
USH2A:usherin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q41
Genomic location:
Preferred name:
NM_206933.4(USH2A):c.12448A>G (p.Thr4150Ala)
HGVS:
  • NC_000001.11:g.215675463T>C
  • NG_009497.1:g.752934A>G
  • NG_009497.2:g.752986A>G
  • NM_206933.4:c.12448A>GMANE SELECT
  • NP_996816.3:p.Thr4150Ala
  • NC_000001.10:g.215848805T>C
  • NM_206933.2:c.12448A>G
Protein change:
T4150A
Links:
dbSNP: rs1172628170
NCBI 1000 Genomes Browser:
rs1172628170
Molecular consequence:
  • NM_206933.4:c.12448A>G - missense variant - [Sequence Ontology: SO:0001583]

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
SCV001448563Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Uncertain significance
(Nov 24, 2020)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).

Sharon D, Ben-Yosef T, Goldenberg-Cohen N, Pras E, Gradstein L, Soudry S, Mezer E, Zur D, Abbasi AH, Zeitz C, Cremers FPM, Khan MI, Levy J, Rotenstreich Y, Birk OS, Ehrenberg M, Leibu R, Newman H, Shomron N, Banin E, Perlman I.

Hum Mutat. 2020 Jan;41(1):140-149. doi: 10.1002/humu.23903. Epub 2019 Sep 15.

PubMed [citation]
PMID:
31456290

Genetic architecture of inherited retinal degeneration in Germany: A large cohort study from a single diagnostic center over a 9-year period.

Weisschuh N, Obermaier CD, Battke F, Bernd A, Kuehlewein L, Nasser F, Zobor D, Zrenner E, Weber E, Wissinger B, Biskup S, Stingl K, Kohl S.

Hum Mutat. 2020 Sep;41(9):1514-1527. doi: 10.1002/humu.24064. Epub 2020 Jun 29.

PubMed [citation]
PMID:
32531858

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001448563.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: USH2A c.12448A>G (p.Thr4150Ala) results in a non-conservative amino acid change located in the Fibronectin type III domain (IPR0003961) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250364 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.12448A>G has been reported in the literature in at-least three individuals, once as a solo allele in a family with Retinitis Pigmentosa (RP), second as a solo complex allele, c.[12448A>G;5012G>A] in a family with RP (Sharon_2020), and third as a compound heterozygous genotype (with c.1841-2A>G) in an individual with sporadic RP (Weisschuh_2020). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=1)/likely pathogenic(n=2). At-least two of these submitters can be traced to an overlapping evidence utilized in the context of this evaluation. 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 27, 2021

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