Submissions for variant NM_000275.3(OCA2):c.1503+5G>A

gnomAD frequency: 0.00008  dbSNP: rs368124046

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193557	SCV000248367	pathogenic	Tyrosinase-positive oculocutaneous albinism	2015-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000302408	SCV000329444	pathogenic	not provided	2023-07-13	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; Published functional studies demonstrate the use of a cryptic splice donor site within intron 14, with sequencing of aberrant transcript demonstrating it results in a frameshift, starting with codon Glycine 502, changing this amino acid to a Valine residue, and creating a premature Stop codon at position 84 of the new reading frame, denoted p.Gly502ValfsX84 (Rimoldi et al., 2014).; This variant is associated with the following publications: (PMID: 15712365, 10649493, 24361966, 31077556)
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000193557	SCV000891285	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2016-05-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000762939	SCV000893362	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2022-04-22	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000193557	SCV002040575	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000302408	SCV002235033	pathogenic	not provided	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the OCA2 gene. It does not directly change the encoded amino acid sequence of the OCA2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs368124046, gnomAD 0.01%). This variant has been observed in individuals with oculocutaneous albinism (PMID: 24361966, 29345414; internal data). ClinVar contains an entry for this variant (Variation ID: 211768). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24361966). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003468884	SCV004208974	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742323	SCV005364737	pathogenic	OCA2-related disorder	2024-09-04	no assertion criteria provided	clinical testing	The OCA2 c.1503+5G>A variant is predicted to interfere with splicing. This intronic variant is predicted to weaken the nearby splice donor site (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). A functional study using RT-PCR analysis confirmed that this variant results in an abnormal mRNA transcript due to splicing errors (Rimoldi et al. 2014. PubMed ID: 24361966). This variant has been reported in multiple individuals with oculocutaneous albinism (Rimoldi et al. 2014. PubMed ID: 24361966; Zhong et al. 2019. PubMed ID: 31077556). Given the evidence, we interpret this variant as pathogenic.