Submissions for variant NM_000275.3(OCA2):c.874T>C (p.Phe292Leu)

gnomAD frequency: 0.00002  dbSNP: rs745573222

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001773844	SCV001992047	uncertain significance	not provided	2021-02-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001773844	SCV002233751	pathogenic	not provided	2024-11-08	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 292 of the OCA2 protein (p.Phe292Leu). This variant is present in population databases (rs745573222, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (internal data). 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: 1305134). 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%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002471142	SCV002766889	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with oculocutaneous albinism, type II (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 24518832, OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from phenylalanine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 and v3) <0.01 for a recessive condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported twice as a VUS in ClinVar and was observed in two unrelated individuals with suspected oculocutaneous albinism and also in an individual with global developmental delay and autism (personal communication - Invitae and GeneDx). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004699454	SCV005204763	uncertain significance	not specified	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.874T>C (p.Phe292Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251496 control chromosomes. 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.874T>C in individuals affected with Oculocutaneous Albinism and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1305134). Based on the evidence outlined above, the variant was classified as uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV005006014	SCV005630597	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-06-18	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003394239	SCV004120520	likely pathogenic	OCA2-related disorder	2024-06-27	no assertion criteria provided	clinical testing	The OCA2 c.874T>C variant is predicted to result in the amino acid substitution p.Phe292Leu. To our knowledge, this variant has not been reported in the literature. Here, at PreventionGenetics, we have detected this variant in the homozygous state in multiple individuals and in the compound heterozygous state along with a pathogenic variant in an individual, all with oculocutaneous albinism (internal data). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. Given the evidence, we interpret c.874T>C (p.Phe292Leu) as likely pathogenic.