Submissions for variant NM_000275.3(OCA2):c.727C>T (p.Arg243Cys)

gnomAD frequency: 0.00018  dbSNP: rs138065338

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000179741	SCV000232038	uncertain significance	not provided	2014-11-20	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118260	SCV001276530	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000179741	SCV001512658	pathogenic	not provided	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 243 of the OCA2 protein (p.Arg243Cys). This variant is present in population databases (rs138065338, gnomAD 0.2%). This missense change has been observed in individual(s) with OCA2-related conditions (PMID: 19865097, 30835348, 32969595, 34838614, 38858617). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 198411). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt OCA2 protein function with a negative predictive value of 80%. 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.
Genome-Nilou Lab	RCV001118260	SCV002040520	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478597	SCV002788147	uncertain significance	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2022-04-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468871	SCV004208971	uncertain significance	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-12-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526627	SCV005039794	uncertain significance	not specified	2024-03-18	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.727C>T (p.Arg243Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0004 in 358298 control chromosomes, predominantly at a frequency of 0.0016 within the East Asian subpopulation in the gnomAD database and at a frequency of 0.0007 within the Japanese population in 108604 control chromosomes in the jMorp database. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.0004 vs 0.0043), allowing no conclusion about variant significance. c.727C>T has been reported in the literature in Chinese or Japanese individuals affected with Oculocutaneous Albinism with heterozygous or compound heterozygous genotypes, with classification of second variants ranging from pathogenic to benign in ClinVar (e.g. Okamura_2021, Wei_2010, Wei_2022). 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: 32969595, 19865097, 34838614, 37930845). ClinVar contains an entry for this variant (Variation ID: 198411). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Breakthrough Genomics, Breakthrough Genomics	RCV000179741	SCV005193651	uncertain significance	not provided		criteria provided, single submitter	not provided
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002478597	SCV005416055	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3_Strong+PP4
PreventionGenetics, part of Exact Sciences	RCV003955089	SCV004776845	uncertain significance	OCA2-related disorder	2024-02-07	no assertion criteria provided	clinical testing	The OCA2 c.727C>T variant is predicted to result in the amino acid substitution p.Arg243Cys. This variant has been reported along with a second OCA2 variant in individuals with oculocutaneous albinism (Wei et al. 2010. PubMed ID: 19865097; Wei et al. 2021. PubMed ID: 34838614). This variant is reported in 0.17% of alleles in individuals of East Asian descent in gnomAD, indicating it is relatively common in this population. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.