Submissions for variant NM_000275.3(OCA2):c.1322A>G (p.Asp441Gly)

gnomAD frequency: 0.00001  dbSNP: rs147816326

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000596631	SCV000709551	uncertain significance	not provided	2017-06-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000596631	SCV001755762	uncertain significance	not provided	2020-07-06	criteria provided, single submitter	clinical testing	Observed in a patient in published literature with oculocutaneous albinism (Shahzad et al., 2017), although it is not stated whether this variant was present in the homozygous or heterozygous state; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28266639)
Genome-Nilou Lab	RCV001797758	SCV002040181	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000596631	SCV002261951	pathogenic	not provided	2024-09-11	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 441 of the OCA2 protein (p.Asp441Gly). This variant is present in population databases (rs147816326, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of oculocutaneous albinism (PMID: 28266639; 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: 502704). 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%. Experimental studies have shown that this missense change affects OCA2 function (PMID: 28266639). This variant disrupts the p.Asp441 amino acid residue in OCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235306	SCV003934424	uncertain significance	not specified	2023-05-31	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1322A>G (p.Asp441Gly) 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 8e-06 in 250048 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1322A>G has been reported in the literature as an uninformative genotype (i.e. zygosity not specified) in at least one affected individual from a family with with Oculocutaneous Albinism (Shahzad_2017). This report does not provide unequivocal conclusions about association of the variant with Oculocutaneous Albinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 28266639). Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either VUS (n=3) or likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003459475	SCV004209001	likely pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2023-09-13	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755088	SCV000882906	likely pathogenic	Nonsyndromic Oculocutaneous Albinism	2017-03-07	no assertion criteria provided	research