NM_206933.4(USH2A):c.3220T>C (p.Trp1074Arg) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 23, 2023
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:: RCV001038387.8

Allele description [Variation Report for NM_206933.4(USH2A):c.3220T>C (p.Trp1074Arg)]

NM_206933.4(USH2A):c.3220T>C (p.Trp1074Arg)

Genes:

USH2A-AS1:USH2A antisense RNA 1 [Gene - HGNC]
USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.3220T>C (p.Trp1074Arg)

HGVS:

NC_000001.11:g.216207369A>G
NG_009497.2:g.221080T>C
NM_007123.6:c.3220T>C
NM_206933.4:c.3220T>CMANE SELECT
NP_009054.6:p.Trp1074Arg
NP_996816.3:p.Trp1074Arg
NC_000001.10:g.216380711A>G
NG_009497.1:g.221028T>C
NM_206933.2:c.3220T>C

Protein change:

W1074R

Links:

dbSNP: rs1344390541

NCBI 1000 Genomes Browser:

rs1344390541

Molecular consequence:

NM_007123.6:c.3220T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_206933.4:c.3220T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001201854	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24944099, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001201854

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 23, 2023)

germline

clinical testing

PubMed (2)
[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

Enrichment of LOVD-USHbases with 152 USH2A genotypes defines an extensive mutational spectrum and highlights missense hotspots.

Baux D, Blanchet C, Hamel C, Meunier I, Larrieu L, Faugère V, Vaché C, Castorina P, Puech B, Bonneau D, Malcolm S, Claustres M, Roux AF.

Hum Mutat. 2014 Oct;35(10):1179-86. doi: 10.1002/humu.22608. Epub 2014 Jul 15.

PubMed [citation]

PMID:: 24944099

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001201854.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

For these reasons, this variant has been classified as Pathogenic. 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 expected to disrupt USH2A protein function. ClinVar contains an entry for this variant (Variation ID: 837118). This missense change has been observed in individual(s) with Usher syndrome (PMID: 24944099). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1074 of the USH2A protein (p.Trp1074Arg).

#	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: Sep 29, 2024

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