Submissions for variant NM_000275.3(OCA2):c.2360C>T (p.Ala787Val)

gnomAD frequency: 0.00004  dbSNP: rs200457227

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	RCV000785611	SCV000924190	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV001093224	SCV001250098	pathogenic	not provided	2020-03-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000785611	SCV002040542	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001093224	SCV002246046	pathogenic	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 787 of the OCA2 protein (p.Ala787Val). This variant is present in population databases (rs200457227, gnomAD 0.01%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 20861488, 23744323, 26165494). 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: 617810). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt OCA2 protein function with a positive predictive value of 80%. This variant disrupts the p.Ala787 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been observed in individuals with OCA2-related conditions (PMID: 22734612), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Centre for Human Genetics, University of Kinshasa	RCV000785611	SCV002558853	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved Alanine residue with a Valine. This change is predicted damaging by the vast majority of prediction algorithms. This variant is very rare with no homozygous in gnomAD (AF: 0.0000239), was submitted to ClinVar by multiple submitters without conflicting interpretation (VCV000617810.16), and is mentioned in multiple publications. Previous ClinVar submissions contain information regarding functional analysis supporting the pathogenic effect of this variant. We identified this variant in a heterozygous state in one patient with Tyrosinase-positive oculocutaneous albinism in the Democratic Republic of Congo (DRC). This patient was heterozygous for the classic 2.7 deletion in the OCA2 gene. Segregation analysis was not performed to unequivocally establish co-segregation with the 2.7 deletion. This variant was classified as pathogenic according to the ACMG guidelines
3billion, Medical Genetics	RCV000785611	SCV002573198	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-09-01	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). The variant is in trans with NM_000275.3:c.2339G>A. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.91). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000617810). The variant is in trans with the other variant. A different missense change at the same codon (p.Ala787Thr) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000803060). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
MGZ Medical Genetics Center	RCV000785611	SCV002581054	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-07-12	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002507318	SCV002795852	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003465674	SCV004209008	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-19	criteria provided, single submitter	clinical testing
GeneDx	RCV001093224	SCV005626999	pathogenic	not provided	2024-07-09	criteria provided, single submitter	clinical testing	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: 10671067, 22734612, Vijayalakshmi2016[Computational], 10671066, 20861488, 26165494, 23744323, 34838614, 36116698, 35741834, 28266639, 20426782, 29345414, 28976636, 32969595)
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755094	SCV000882912	likely pathogenic	Nonsyndromic Oculocutaneous Albinism	2017-03-07	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004742625	SCV005345458	likely pathogenic	OCA2-related disorder	2024-03-22	no assertion criteria provided	clinical testing	The OCA2 c.2360C>T variant is predicted to result in the amino acid substitution p.Ala787Val. This variant has been reported as causative for autosomal recessive oculocutaneous albinism (Oetting et al. 1998. PubMed ID: 10671067; Wei et al. 2015. PubMed ID: 26165494; Shahzad et al. 2017. PubMed ID: 28266639). Alternate substitutions of this amino acid (p.Ala787Glu and p.Ala787Thr) have been reported in individuals with oculocutaneous albinism (Shahzad et al. 2017. PubMed ID: 28266639; Marti et al. 2017. PubMed ID: 28976636). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. Given the evidence, we interpret this variant as likely pathogenic.