NM_206933.4(USH2A):c.11927C>T (p.Thr3976Met) AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: May 10, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000041707.12

Allele description [Variation Report for NM_206933.4(USH2A):c.11927C>T (p.Thr3976Met)]

NM_206933.4(USH2A):c.11927C>T (p.Thr3976Met)

Gene:
USH2A:usherin [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q41
Genomic location:
Preferred name:
NM_206933.4(USH2A):c.11927C>T (p.Thr3976Met)
HGVS:
  • NC_000001.11:g.215728169G>A
  • NG_009497.1:g.700228C>T
  • NG_009497.2:g.700280C>T
  • NM_206933.4:c.11927C>TMANE SELECT
  • NP_996816.3:p.Thr3976Met
  • NC_000001.10:g.215901511G>A
  • NM_206933.2:c.11927C>T
  • NM_206933.3:c.11927C>T
  • O75445:p.Thr3976Met
  • c.11927C>T
Protein change:
T3976M
Links:
UniProtKB: O75445#VAR_054609; dbSNP: rs142381713
NCBI 1000 Genomes Browser:
rs142381713
Molecular consequence:
  • NM_206933.4:c.11927C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
7

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
SCV000065403Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Likely benign
(May 5, 2016)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000605543ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Uncertain significance
(May 10, 2019)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided77not providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular and in silico analyses of the full-length isoform of usherin identify new pathogenic alleles in Usher type II patients.

Baux D, Larrieu L, Blanchet C, Hamel C, Ben Salah S, Vielle A, Gilbert-Dussardier B, Holder M, Calvas P, Philip N, Edery P, Bonneau D, Claustres M, Malcolm S, Roux AF.

Hum Mutat. 2007 Aug;28(8):781-9.

PubMed [citation]
PMID:
17405132

Ex vivo splicing assays of mutations at noncanonical positions of splice sites in USHER genes.

Le Guédard-Méreuze S, Vaché C, Baux D, Faugère V, Larrieu L, Abadie C, Janecke A, Claustres M, Roux AF, Tuffery-Giraud S.

Hum Mutat. 2010 Mar;31(3):347-55. doi: 10.1002/humu.21193.

PubMed [citation]
PMID:
20052763
See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000065403.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided7not providednot providedclinical testing PubMed (3)

Description

p.Thr3976Met in exon 61 of USH2A: This variant is not expected to have clinical significance because it occurs in cis with a pathogenic variant in one individua l with Usher syndrome (Baux 2007, Le Guedard-Mereuze 2010). It has been identifi ed in 0.1% (56/66702) of European chromosomes by the Exome Aggregation Consortiu m (ExAC, http://exac.broadinstitute.org; dbSNP rs142381713).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided7not provided7not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605543.2

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

Description

The p.Thr3976Met variant (rs142381713) has been observed as part of a complex allele with a different variant, c.3811+3A>T, found in an individual with a clinical diagnosis of Usher syndrome type II (Baux 2007). In addition to this complex allele, the patient in Baux (2007) also carried a clearly pathogenic nonsense variant (p.Leu2301Ter) in trans. Subsequent in vitro analysis of the c.3811+3A>T variant indicated that it almost completely disrupts splicing, leading to skipping of exon 17 (Le Guedard-Mereuze 2010). The c.3811+3A>T variant is also absent from population databases such as 1000 Genomes, the NHLBI GO Exome Sequencing Project (ESP), and the Exome Aggregation Consortium (ExAC) browser. As a comparison, p.Thr3976Met is listed in the ESP with an allele frequency in European Americans of 0.14% (identified in 12 out of 8,600 chromosomes), and in the ExAC browser with an allele frequency in non-Finnish Europeans of 0.08% (identified in 56 out of 66,702 chromosomes). These observations argue that the c.3811+3A>T is pathogenic, and thus it is likely that the p.Thr3976Met variant is not. However, skipping of exon 17 retains the reading frame of USH2A mRNA, and the c.3811+3A>T variant has not been reported with any other pathogenic alleles. Moreover, the threonine at codon 3976 is highly conserved considering 10 species up to chicken (Alamut software v2.7.1), and computational analyses suggest the p.Thr3976Met variant has a significant effect on USH2A protein structure/function (SIFT: damaging, PolyPhen2: probably damaging, and Mutation Taster: disease causing). Therefore, with the uncertainty concerning the pathogenicity of the c.3811+3A>T variant, and the lack of other evidence suggesting the p.Thr3976Met variant is benign, the clinical significance of the p.Thr3976Met variant cannot be determined with certainty.

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

Last Updated: Nov 27, 2021

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