Submissions for variant NM_000275.3(OCA2):c.1001C>T (p.Ala334Val)

gnomAD frequency: 0.00001  dbSNP: rs121918168

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001851522	SCV002237062	pathogenic	not provided	2021-09-24	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with valine at codon 334 of the OCA2 protein (p.Ala334Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with ocular albinism (PMID: 10649493, 29345414). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 958). 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. For these reasons, this variant has been classified as Pathogenic.
3billion	RCV000001009	SCV002318841	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic (ClinVar ID: VCV000000958, PMID:10649493). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.742>=0.6). A missense variant is a common mechanism. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000080). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Centre for Human Genetics, University of Kinshasa	RCV000001009	SCV002558851	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: 0.00000797), was submited in ClinVar by multiple submitters without conflicting interpretation (VCV000000958.3), and is mentioned in at least two publications (PMID: 29345414‚ PMID: 10649493). 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.
Revvity Omics, Revvity	RCV001851522	SCV003814239	uncertain significance	not provided	2021-04-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003466773	SCV004209032	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-05-22	criteria provided, single submitter	clinical testing
OMIM	RCV000001009	SCV000021159	pathogenic	Tyrosinase-positive oculocutaneous albinism	2000-01-01	no assertion criteria provided	literature only