Submissions for variant NM_000275.3(OCA2):c.1182+1G>A

gnomAD frequency: 0.00014  dbSNP: rs371963034

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502094	SCV000596154	pathogenic	Tyrosinase-positive oculocutaneous albinism	2017-04-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001550696	SCV001771070	pathogenic	not provided	2023-04-13	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame deletion of exon 11; Deletions involving coding exons in this gene are frequently reported as pathogenic, regardless of frame prediction (HGMD); This variant is associated with the following publications: (PMID: 25525159, 28976636, 31196117, 31229681, 34838614, 31077556, 21458243)
Revvity Omics, Revvity	RCV001550696	SCV002020571	pathogenic	not provided	2019-08-14	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000502094	SCV002040598	pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001550696	SCV002231333	pathogenic	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 11 of the OCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in OCA2 are known to be pathogenic (PMID: 19865097, 21541274). This variant is present in population databases (rs371963034, gnomAD 0.06%). Disruption of this splice site has been observed in individuals with oculocutaneous albinism (PMID: 28976636, 31077556). ClinVar contains an entry for this variant (Variation ID: 436099). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV000502094	SCV002581053	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-07-12	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003464075	SCV004208982	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001550696	SCV005051550	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	OCA2: PM3:Very Strong, PVS1:Strong, PM2
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV000502094	SCV005417384	pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing	PVS1_Moderate+PM2_Supporting+PM3_VeryStrong+PP4
Fulgent Genetics, Fulgent Genetics	RCV005010435	SCV005630584	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003424061	SCV004117142	pathogenic	OCA2-related disorder	2024-04-18	no assertion criteria provided	clinical testing	The OCA2 c.1182+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been reported in the homozygous and compound heterozygous states in individuals with oculocutaneous albinism (Marti et al. 2018. PubMed ID: 28976636; Zhong et al. 2019. PubMed ID: 31077556). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD. Variants that disrupt the consensus splice donor site in OCA2 are expected to be pathogenic, and this variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/436099/). Given all the evidence, we interpret c.1182+1G>A as pathogenic.