ClinVar Miner

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

gnomAD frequency: 0.00005  dbSNP: rs121918169
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Total submissions: 11
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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

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