NM_206933.4(USH2A):c.8790T>G (p.Asn2930Lys) AND not provided

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2022
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001811643.15

Allele description [Variation Report for NM_206933.4(USH2A):c.8790T>G (p.Asn2930Lys)]

NM_206933.4(USH2A):c.8790T>G (p.Asn2930Lys)

Gene:

USH2A:usherin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q41

Genomic location:

Preferred name:

NM_206933.4(USH2A):c.8790T>G (p.Asn2930Lys)

HGVS:

NC_000001.11:g.215867062A>C
NG_009497.2:g.561387T>G
NM_206933.4:c.8790T>GMANE SELECT
NP_996816.3:p.Asn2930Lys
NC_000001.10:g.216040404A>C
NG_009497.1:g.561335T>G
NM_206933.2:c.8790T>G

Protein change:

N2930K

Links:

dbSNP: rs754774098

NCBI 1000 Genomes Browser:

rs754774098

Molecular consequence:

NM_206933.4:c.8790T>G - 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
SCV001471629	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Uncertain significance (Aug 18, 2019)	germline	clinical testing	Citation Link,
SCV003253021	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 13, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 20507924, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001471629

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Uncertain significance
(Aug 18, 2019)

germline

clinical testing

Citation Link,

SCV003253021

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 13, 2022)

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

Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa.

McGee TL, Seyedahmadi BJ, Sweeney MO, Dryja TP, Berson EL.

J Med Genet. 2010 Jul;47(7):499-506. doi: 10.1136/jmg.2009.075143. Epub 2010 May 27.

PubMed [citation]

PMID:: 20507924
PMCID:: PMC3070405

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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001471629.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The USH2A c.8790T>G; p.Asn2930Lys variant (rs754774098) is reported in the literature in several individuals affected with retinitis pigmentosa, although it was not demonstrated to be disease-causing in these individuals (McGee 2010). This variant is found in the general population with an overall allele frequency of 0.004% (10/282720 alleles) in the Genome Aggregation Database. The asparagine at codon 2930 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. However, due to limited information, the clinical significance of the p.Asn2930Lys variant is uncertain at this time. References: McGee TL et al. Novel mutations in the long isoform of the USH2A gene in patients with Usher syndrome type II or non-syndromic retinitis pigmentosa. J Med Genet. 2010 Jul;47(7):499-506.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003253021.1

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

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 2930 of the USH2A protein (p.Asn2930Lys). This variant is present in population databases (rs754774098, gnomAD 0.02%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 20507924). ClinVar contains an entry for this variant (Variation ID: 866103). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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: Nov 10, 2024

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