NM_000329.3(RPE65):c.1555G>A (p.Glu519Lys) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Oct 5, 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:: RCV001994112.6

Allele description [Variation Report for NM_000329.3(RPE65):c.1555G>A (p.Glu519Lys)]

NM_000329.3(RPE65):c.1555G>A (p.Glu519Lys)

Gene:

RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.3

Genomic location:

Preferred name:

NM_000329.3(RPE65):c.1555G>A (p.Glu519Lys)

HGVS:

NC_000001.11:g.68429823C>T
NG_008472.2:g.25137G>A
NM_000329.3:c.1555G>AMANE SELECT
NP_000320.1:p.Glu519Lys
NC_000001.10:g.68895506C>T

Protein change:

E519K

Links:

dbSNP: rs373274945

NCBI 1000 Genomes Browser:

rs373274945

Molecular consequence:

NM_000329.3:c.1555G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Leber congenital amaurosis 2 (LCA2)
Synonyms:: AMAUROSIS CONGENITA OF LEBER II; Amaurosis congenita of Leber, type 2; RPE65-Related Leber Congenital Amaurosis
Identifiers:: MONDO: MONDO:0008765; MedGen: C1859844; Orphanet: 65; OMIM: 204100

Name:: Retinitis pigmentosa 20 (RP20)
Synonyms:: RP 20
Identifiers:: MONDO: MONDO:0013425; MedGen: C3151086; Orphanet: 791; OMIM: 613794

Recent activity

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Odorant binding protein 2A [Homo sapiens]
Odorant binding protein 2A [Homo sapiens]
gi|47479498|gb|AAH69563.1|

Protein
ART4 [Chlamydotis macqueenii]
ART4 [Chlamydotis macqueenii]
Gene ID:104478793

Gene
Neoplastic Cells, Circulating
Neoplastic Cells, Circulating
Exfoliate neoplastic cells circulating in the blood and associated with metastasizing tumors.<br/>Year introduced: 2009 (1965)

MeSH
Anticestodal Agents [Pharmacological Action]
Anticestodal Agents [Pharmacological Action]

MeSH
Chondrosarcoma
Chondrosarcoma
A slowly growing malignant neoplasm derived from cartilage cells, occurring most frequently in pelvic bones or near the ends of long bones, in middle-aged and old people. Most...<br/>

MeSH

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002262256	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 5, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002262256

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 5, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV002262256.3

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

Description

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 519 of the RPE65 protein (p.Glu519Lys). This variant is present in population databases (rs373274945, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with RPE65-related conditions. ClinVar contains an entry for this variant (Variation ID: 1481159). 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 RPE65 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: Sep 29, 2024

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