Submissions for variant NM_000275.3(OCA2):c.1842+1G>T

gnomAD frequency: 0.00001  dbSNP: rs387906240

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001851521	SCV002242136	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 17 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 not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of oculocutaneous albinism and/or oculocutaneous albinism (PMID: 8302318, 28451379; Invitae). ClinVar contains an entry for this variant (Variation ID: 953). 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.
GeneDx	RCV001851521	SCV002569495	pathogenic	not provided	2022-01-31	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28451379, 27468418, 8302318, 25525159, 18463683)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323345	SCV004030146	likely pathogenic	Oculocutaneous albinism	2023-07-31	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1842+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.2e-05 in 31404 control chromosomes (gnomAD). c.1842+1G>T has been reported in the literature as a compound heterozygous genotype in at least two individuals affected with Oculocutaneous Albinism (e.g. Lee_1994, Gao_2017). These data indicate that the variant may 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: 28451379, 18463683, 8302318). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
OMIM	RCV000001004	SCV000021154	pathogenic	Tyrosinase-positive oculocutaneous albinism	1994-02-24	no assertion criteria provided	literature only