Submissions for variant NM_000275.3(OCA2):c.1239+5G>C

gnomAD frequency: 0.00016  dbSNP: rs757119713

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724356	SCV000225497	uncertain significance	not provided	2014-11-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000724356	SCV000573300	pathogenic	not provided	2024-04-08	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 both splice predictors and evolutionary conservation support a deleterious effect, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Fang2022[Abstract])
Fulgent Genetics, Fulgent Genetics	RCV000763954	SCV000894901	uncertain significance	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2018-10-31	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001797659	SCV002039981	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818417	SCV002069185	uncertain significance	not specified	2018-06-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000724356	SCV002210356	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 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 (rs757119713, gnomAD 0.0009%). This variant has been observed in individuals with clinical features of oculocutaneous albinism (Invitae). ClinVar contains an entry for this variant (Variation ID: 193985). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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.
Baylor Genetics	RCV003462277	SCV004208994	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818417	SCV004241537	uncertain significance	not specified	2023-12-15	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1239+5G>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens the canonical 5' donor site and three predict the variant abolishes a downstream cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251376 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1239+5G>C in individuals affected with Oculocutaneous Albinism and no experimental evidence demonstrating its impact on protein function have been reported in the literature. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as uncertain significance and two submitters, one citing internal data, classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.