Submissions for variant NM_000275.3(OCA2):c.2037G>C (p.Trp679Cys)

gnomAD frequency: 0.00005  dbSNP: rs121918169

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001093225	SCV001250099	pathogenic	not provided	2016-08-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000001011	SCV001423799	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2020-03-02	criteria provided, single submitter	clinical testing	The OCA2 c.2037G>C (p.Trp679Cys) variant is a missense variant that has been reported in a compound heterozygous state with a second variant in trans in at least three unrelated individuals diagnosed with oculocutaneous albinism type 2 (Passmore et al. 1999; King et al. 2003; Simeonov et al. 2013). The variant, along with a second variant in the OCA2 gene, was also reported in an individual with a personal and family history of melanoma but no reported signs of oculocutaneous albinism; the phase of the two variants is unknown (Potjer et al. 2019). Another variant at the same amino acid residue, p.Tyr679Arg, was identified in a hemizygous state with a deletion of chromosome 15q in an individual diagnosed with oculocutaneous albinism type 2 and Prader-Willi syndrome (Lee et al. 1994). The p.Tyr679Cys variant is reported at a frequency of 0.000277 in the European (Finnish) population of the Genome Aggregation Consortium. Multiple in silico analyses predict that this variant is deleterious. Based on the available evidence and the application of ACMG criteria, the p.Tyr679Cys variant is classified as likely pathogenic for oculocutaneous albinism type 2.
GeneDx	RCV001093225	SCV001824941	likely pathogenic	not provided	2024-06-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23504663, 12876664, 10987646, 23824587, 30414346, 7874125, 33050356, 31429209)
Genome-Nilou Lab	RCV000001011	SCV002039643	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001093225	SCV002072172	likely pathogenic	not provided	2017-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001093225	SCV002236383	pathogenic	not provided	2025-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 679 of the OCA2 protein (p.Trp679Cys). This variant is present in population databases (rs121918169, gnomAD 0.03%). This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 10987646, 12876664, 23504663). 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: 960). 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.
MGZ Medical Genetics Center	RCV000001011	SCV002580170	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-06-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317027	SCV004020537	likely pathogenic	Oculocutaneous albinism	2023-06-06	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.2037G>C (p.Trp679Cys) results in a non-conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.2e-05 in 251266 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (0.0043), allowing no conclusion about variant significance. The variant, c.2037G>C, has been reported in the literature in multiple compound heterozygous individuals affected with Oculocutaneous Albinism (e.g. King_2003, Passmore_1999, Simeonov_2013, Kessel_2021). These data indicate that the variant is likely to be associated with disease. In addition, this variant was also reported in heterozygous individuals affected with melanoma (e.g. Potjer_2019, Stolarova_2020) and retinal disease (Holtan_2020), however the significance of these findings is unclear. 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: 12876664, 10987646, 23504663, 30414346, 31429209, 33050356, 33612058). Eight submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=5) or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001262139	SCV004209023	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-07-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005007802	SCV005630558	likely pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-06-20	criteria provided, single submitter	clinical testing
OMIM	RCV000001011	SCV000021161	pathogenic	Tyrosinase-positive oculocutaneous albinism	2003-09-01	no assertion criteria provided	literature only