Submissions for variant NM_000275.3(OCA2):c.2324G>A (p.Gly775Asp)

dbSNP: rs987780496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001048856	SCV001212881	pathogenic	not provided	2024-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 775 of the OCA2 protein (p.Gly775Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with oculocutaneous albinism (PMID: 20019752). ClinVar contains an entry for this variant (Variation ID: 845735). 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 with a positive predictive value of 80%. This variant disrupts the p.Gly775 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (PMID: 17385796, 18683130), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001048856	SCV002067461	pathogenic	not provided	2020-04-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the OCA2 gene demonstrated a homozygous sequence change, c.2324G>A, in exon 22 that results in an amino acid change, p.Gly775Asp. This sequence change is absent from known population databases (gnomAD). The p.Gly775Asp change affects a highly conserved amino acid residue located in a domain of the OCA2 protein that is known to be functional. The p.Gly775Asp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, REVEL). This sequence change has been previously reported in the homozygous state in more than 12 individuals with ocular albinism, all of whom originated from the South Pacific region. The authors suggested that this sequence change may be a “Polynesian Islander-” specific mutation” (PMID: 20019752). Furthermore, other amino acid changes at this same positon (p.Gly77Ser, p.Gly775Arg) have also been reported in patients with ocular albinism (PMIDs: 18683130, 21541274, 17385796). We interpret this sequence change as pathogenic.
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV003128258	SCV003804561	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003467756	SCV004209038	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-11	criteria provided, single submitter	clinical testing
GeneDx	RCV001048856	SCV005326997	likely pathogenic	not provided	2024-03-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29345414, 37650133, 35870188, 20019752)
Fulgent Genetics, Fulgent Genetics	RCV005012483	SCV005630544	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-05-08	criteria provided, single submitter	clinical testing