Submissions for variant NM_000275.3(OCA2):c.2228C>T (p.Pro743Leu)

gnomAD frequency: 0.00023  dbSNP: rs121918167

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000481371	SCV000227759	pathogenic	not provided	2015-02-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000481371	SCV000568221	pathogenic	not provided	2022-07-11	criteria provided, single submitter	clinical testing	In an animal model, pigs homozygous for an orthologous variant in OCA2 exhibited pigmentation-related defects similar to the oculocutaneous albinism phenotype in humans (Zhang et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 8302318, 18463683, 22734612, 10649493, 20426782, 28451379, 12876664, 28266639, 31636960, 31980526, 31589614, 31077556)
Fulgent Genetics, Fulgent Genetics	RCV000762938	SCV000893361	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-01-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000001007	SCV000966901	pathogenic	Tyrosinase-positive oculocutaneous albinism	2018-07-18	criteria provided, single submitter	clinical testing	The p.Pro743Leu variant in Oculocutaneous albinism type 2 (OCA type 2) has been reported in the homozygous or compound heterozygous state in >7 individuals with oculocutaneous albinism (OCA) type 2 and segregated with disease in 9 affected relatives from 2 families (Lee 1994, Hutton 2008, Sengupta 2010, Jaworek 2012, S hahzad 2017). This variant has also been reported in ClinVar (Variation ID# 956) . This variant has been identified in 0.04% (9/24018) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121918167). This frequency is consistent with the carrier frequency for Oculo cutaneous albinism type 2. Computational prediction tools and conservation analy sis suggest that this variant may impact the protein. In summary, this variant m eets criteria to be classified as pathogenic for Oculocutaneous albinism type 2 in an autosomal recessive manner based upon multiple occurrences with pathogenic OCA2 variants in individuals with Oculocutaneous albinism and segregation with disease in multiple families. ACMG/AMP Criteria applied: PM3_VeryStrong; PM2; PP 1_Moderate; PP3.
Revvity Omics, Revvity	RCV000481371	SCV002020184	likely pathogenic	not provided	2019-05-08	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000001007	SCV002040553	pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000481371	SCV002070486	pathogenic	not provided	2018-05-15	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000481371	SCV002131064	pathogenic	not provided	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 743 of the OCA2 protein (p.Pro743Leu). This variant is present in population databases (rs121918167, gnomAD 0.04%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 8302318, 28266639, 31077556). 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: 956). 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 expected to disrupt OCA2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001007	SCV002767980	pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism and oculocutaneous, type II albinism (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene causing oculocutaneous albininism are known to have variable expressivity (PMID: 24518832) (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to leucine. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2) (38 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated citrate transporter domain (Pfam). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in >15 oculocutaneous albinism (OCA) type 2 patients, in both the homozygous and compound heterozygous state (ClinVar; PMIDs: 20426782; 31077556; 24845642; 8302318; 7874125; 12876664; 18463683; 22734612; 24118800; 27734839; 31229681). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Neuberg Centre For Genomic Medicine, NCGM	RCV000001007	SCV004101476	pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing	The missense variant c.2228C>T(p.Pro743Leu) has been reported in homozygous or compound heterozygous state in >7 individuals with oculocutaneous albinism (OCA) type 2 and segregated with disease in 9 affected relatives from 2 families (Sengupta et al. 2010, Shahzad et al. 2017). This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic. The p.Pro743Leu variant is novel (not in any individuals) in 1000 Genomes. The amino acid Pro at position 743 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Pro743Leu in OCA2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460401	SCV004208976	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-27	criteria provided, single submitter	clinical testing
OMIM	RCV000001007	SCV000021157	pathogenic	Tyrosinase-positive oculocutaneous albinism	1994-02-24	no assertion criteria provided	literature only
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755092	SCV000882910	likely pathogenic	Nonsyndromic Oculocutaneous Albinism	2017-03-07	no assertion criteria provided	research