NM_000275.3(OCA2):c.1453G>A (p.Gly485Arg) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Oct 16, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV001820933.7

Allele description

NM_000275.3(OCA2):c.1453G>A (p.Gly485Arg)

Gene:

OCA2:OCA2 melanosomal transmembrane protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q13.1

Genomic location:

Preferred name:

NM_000275.3(OCA2):c.1453G>A (p.Gly485Arg)

HGVS:

NC_000015.10:g.27983395C>T
NG_009846.1:g.120918G>A
NM_000275.3:c.1453G>AMANE SELECT
NM_001300984.2:c.1381G>A
NP_000266.2:p.Gly485Arg
NP_001287913.1:p.Gly461Arg
NC_000015.9:g.28228541C>T
NM_000275.2:c.1453G>A

Protein change:

G461R

Links:

dbSNP: rs747214535

NCBI 1000 Genomes Browser:

rs747214535

Molecular consequence:

NM_000275.3:c.1453G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001300984.2:c.1381G>A - 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
SCV002069095	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 16, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003443451	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Oct 16, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18821858, 29345414, 20806075, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002069095

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 16, 2018)

germline

clinical testing

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

SCV003443451

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Oct 16, 2022)

germline

clinical testing

PubMed (4)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Molecular diagnosis of oculocutaneous albinism: new mutations in the OCA1-4 genes and practical aspects.

Rooryck C, Morice-Picard F, Elçioglu NH, Lacombe D, Taieb A, Arveiler B.

Pigment Cell Melanoma Res. 2008 Oct;21(5):583-7. doi: 10.1111/j.1755-148X.2008.00496.x. No abstract available.

PubMed [citation]

PMID:: 18821858

See all PubMed Citations (5)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002069095.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003443451.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

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. This variant disrupts the p.Gly485 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (PMID: 18821858, 29345414), which suggests that this may be a clinically significant amino acid residue. 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 OCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 315466). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 20806075). This variant is present in population databases (rs747214535, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 485 of the OCA2 protein (p.Gly485Arg).

#	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: Aug 18, 2024

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