ClinVar Miner

Submissions for variant NM_000275.3(OCA2):c.2207C>T (p.Ser736Leu)

gnomAD frequency: 0.00003  dbSNP: rs780296175
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000724171 SCV000227760 uncertain significance not provided 2014-10-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000192656 SCV000248369 likely pathogenic Tyrosinase-positive oculocutaneous albinism 2015-06-16 criteria provided, single submitter clinical testing
GeneDx RCV000724171 SCV000617266 likely pathogenic not provided 2024-05-15 criteria provided, single submitter clinical testing Observed with a variant of uncertain significance or as a single heterozygous variant in additional patients in published literature (PMID: 9259203, 15173252, 29345414, 28976636); 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: 28976636, 18463683, 9259203, 15173252, 29345414, 24845642, 31501239)
Genome-Nilou Lab RCV000192656 SCV002040930 uncertain significance Tyrosinase-positive oculocutaneous albinism 2021-11-07 criteria provided, single submitter clinical testing
Invitae RCV000724171 SCV002247451 pathogenic not provided 2024-01-17 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 736 of the OCA2 protein (p.Ser736Leu). This variant is present in population databases (rs780296175, gnomAD 0.004%). This missense change has been observed in individuals with clinical features of oculocutaneous albinism (PMID: 18463683, 28976636, 29345414; Invitae). ClinVar contains an entry for this variant (Variation ID: 195557). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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 RCV000192656 SCV002766792 likely pathogenic Tyrosinase-positive oculocutaneous albinism 2022-03-31 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as likely pathogenic. The following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism (MIM#203200) and 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 serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (V2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and very highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated citrate transporter domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least 5 individuals with oculocutaneous albinism (ClinVar, PMID: 28976636, 18463683, 9259203, 24845642, 15173252). It has also been reported as VUS in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences RCV003407649 SCV004115960 pathogenic OCA2-related disorder 2023-11-29 criteria provided, single submitter clinical testing The OCA2 c.2207C>T variant is predicted to result in the amino acid substitution p.Ser736Leu. This variant has been reported in individuals with oculocutaneous albinism (Spritz et al. 1997. PubMedID: 9259203; Garrison et al. 2004. PubMedID: 15173252; Marti et al. 2018. PubMed ID: 28976636). At PreventionGenetics, we have observed this variant in the homozygous and compound heterozygous states in additional patients with OCA and hypopigmentation disorders (internal data). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Given the evidence, we interpret c.2207C>T (p.Ser736Leu) as pathogenic.
Baylor Genetics RCV003468858 SCV004209024 likely pathogenic SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES 2023-12-07 criteria provided, single submitter clinical testing

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