Submissions for variant NM_000275.3(OCA2):c.287A>C (p.Glu96Ala)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058454	SCV003442808	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 96 of the OCA2 protein (p.Glu96Ala). This variant is present in population databases (rs748287294, gnomAD 0.003%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 19060277, 27734839, 29345414; Invitae). 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: 2137638). 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.Glu96 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003331419	SCV004037610	likely pathogenic	Oculocutaneous albinism	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.287A>C (p.Glu96Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251472 control chromosomes (gnomAD). c.287A>C has been reported in the literature in individuals affected with Oculocutaneous Albinism (examples: Gronskov_2009, Lasseaux_2018, Mauri_2017, Kessel_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 19060277, 33612058, 29345414, 27734839). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV003465926	SCV004209047	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-11-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003418721	SCV004115014	likely pathogenic	OCA2-related disorder	2023-11-29	no assertion criteria provided	clinical testing	The OCA2 c.287A>C variant is predicted to result in the amino acid substitution p.Glu96Ala. This variant has been reported in both the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (Grønskov et al 2009. PubMed ID: 19060277; Mauri et al. 2016. PubMed ID: 27734839; Table S3 in Lasseaux et al. 2018. PubMed ID: 29345414). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret c.287A>C (p.Glu96Ala) as likely pathogenic.