Submissions for variant NM_000275.3(OCA2):c.2363C>T (p.Ser788Leu)

gnomAD frequency: 0.00004  dbSNP: rs147736385

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000851380	SCV001274690	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2017-07-31	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV001578073	SCV001805600	pathogenic	not provided	2020-07-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: reduced melanin content in transfected cells (Wu et al., 2020). Clinical manifestations of oculocutaneous albinism were also observed in rhesus macaques with the variant in the homozygous state (Wu et al., 2020).; This variant is associated with the following publications: (PMID: 31196117, 32259106, 31229681, 23824587)
Genome-Nilou Lab	RCV000851380	SCV002040047	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Invitae	RCV001578073	SCV002237816	pathogenic	not provided	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 788 of the OCA2 protein (p.Ser788Leu). This variant is present in population databases (rs147736385, gnomAD 0.006%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 31196117, 31813138; SOURCE: 31813138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 627604). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on OCA2 protein function. This variant disrupts the p.Ser788 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (PMID: 29345414), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003465688	SCV004209016	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-08-10	criteria provided, single submitter	clinical testing
Center of Medical Genetics, Central South University	RCV000851380	SCV000902471	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2019-03-26	no assertion criteria provided	clinical testing