NM_206933.4(USH2A):c.10999A>C (p.Thr3667Pro) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jan 7, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002515601.3

Allele description [Variation Report for NM_206933.4(USH2A):c.10999A>C (p.Thr3667Pro)]

NM_206933.4(USH2A):c.10999A>C (p.Thr3667Pro)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.10999A>C (p.Thr3667Pro)

HGVS:

NC_000001.11:g.215766729T>G
NG_009497.2:g.661720A>C
NM_206933.4:c.10999A>CMANE SELECT
NP_996816.3:p.Thr3667Pro
NC_000001.10:g.215940071T>G
NG_009497.1:g.661668A>C
NM_206933.2:c.10999A>C

Protein change:

T3667P

Links:

dbSNP: rs150822759

NCBI 1000 Genomes Browser:

rs150822759

Molecular consequence:

NM_206933.4:c.10999A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003297793	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 7, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23967202, 28041643, 31213501, 36284460, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003297793

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 7, 2024)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Targeted exon sequencing successfully discovers rare causative genes and clarifies the molecular epidemiology of Japanese deafness patients.

Miyagawa M, Naito T, Nishio SY, Kamatani N, Usami S.

PLoS One. 2013;8(8):e71381. doi: 10.1371/journal.pone.0071381.

PubMed [citation]

PMID:: 23967202
PMCID:: PMC3742761

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease.

Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, et al.

Am J Hum Genet. 2017 Jan 5;100(1):75-90. doi: 10.1016/j.ajhg.2016.12.003. Epub 2016 Dec 29.

PubMed [citation]

PMID:: 28041643
PMCID:: PMC5223092

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003297793.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3667 of the USH2A protein (p.Thr3667Pro). This variant is present in population databases (rs150822759, gnomAD 0.05%). This missense change has been observed in individuals with clinical features of USH2A-related conditions (PMID: 23967202, 28041643, 31213501, 36284460). ClinVar contains an entry for this variant (Variation ID: 225512). 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 not expected to disrupt USH2A protein function with a negative predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Jan 19, 2025

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