Submissions for variant NM_000275.3(OCA2):c.1211C>T (p.Thr404Met)

gnomAD frequency: 0.00023  dbSNP: rs144812594

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193262	SCV000248364	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2015-02-26	criteria provided, single submitter	clinical testing
GeneDx	RCV000413048	SCV000491125	likely pathogenic	not provided	2023-07-27	criteria provided, single submitter	clinical testing	Observed as a single heterozygous variant or with a variant of uncertain significance, phase unknown, in patients with oculocutaneous albinism in published literature (Gronskov et al., 2009, Simeonov et al., 2013; Rimoldi et al., 2014); 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: 23824587, 33144682, 24361966, 28266639, 23504663, 27734839, 36116698, 7762554, 34838614, 29345414, 19060277)
Genome-Nilou Lab	RCV000193262	SCV002039992	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413048	SCV002133653	pathogenic	not provided	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 404 of the OCA2 protein (p.Thr404Met). This variant is present in population databases (rs144812594, gnomAD 0.07%). This missense change has been observed in individual(s) with ocular albinism (PMID: 23504663, 24361966, 27734839). 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: 211766). 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.
3billion, Medical Genetics	RCV000193262	SCV002521137	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.008%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.96; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000211766). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Centre for Human Genetics, University of Kinshasa	RCV000193262	SCV002558852	pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces a conserved Threonine residue with a Methionine. This change is predicted damaging by the vast majority of prediction algorithms. This variant is very rare with no homozygous in gnomAD (AF: 0.0000636), was submitted to ClinVar by multiple submitters mostly classifying this variant as pathogenic/Likely pathogenic (VCV000211766.10), and is mentioned in at least three publications (PMID: 29345414‚ PMID: 10649493). Previous ClinVar submissions contain information regarding functional analysis demonstrating the pathogenic role of this variant. We identified this variant in a heterozygous state in one patient with Tyrosinase-positive oculocutaneous albinism in the Democratic Republic of Congo (DRC). This patient was heterozygous for the classic 2.7 deletion in the OCA2 gene. segregation analysis showed that the variant was in trans to the deletion in our patient. This variant was classified as pathogenic according to the ACMG guidelines
PreventionGenetics, part of Exact Sciences	RCV003401054	SCV004109991	pathogenic	OCA2-related disorder	2023-02-28	criteria provided, single submitter	clinical testing	The OCA2 c.1211C>T variant is predicted to result in the amino acid substitution p.Thr404Met. This variant has been reported in the compound heterozygous and homozygous states in individuals with oculocutaneous albinism (OCA) (Rimoldi et al. 2014. PubMed ID: 24361966; Shahzad et al. 2017. PubMed ID: 28266639). This variant has also been reported in a patient with OCA, but a second causative variant was not found (Grønskov et al. 2009. PubMed ID: 19060277, Table 3). At PreventionGenetics, this variant along with a second pathogenic variant has been found in several affected individuals. This variant is classified as likely pathogenic by several independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/211766/). Given the evidence, we classify c.1211C>T (p.Thr404Met) as pathogenic.
Baylor Genetics	RCV003462301	SCV004208981	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767132	SCV005380958	likely pathogenic	Oculocutaneous albinism	2024-08-16	criteria provided, single submitter	clinical testing	Variant summary: OCA2 c.1211C>T (p.Thr404Met) 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 6.4e-05 in 251456 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in OCA2 causing Oculocutaneous Albinism (6.4e-05 vs 0.0043), allowing no conclusion about variant significance. c.1211C>T has been reported in the literature in the presumed compound heterozygous state in multiple individuals affected with Oculocutaneous Albinism (example, Mauri_2017, Wei_2022, Simeonov_2013). These data indicate that the variant is likely to be associated with disease. 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: 27734839, 24361966, 28266639, 23504663, 34838614). ClinVar contains an entry for this variant (Variation ID: 211766). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV005003550	SCV005630581	pathogenic	Tyrosinase-positive oculocutaneous albinism; SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-25	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000755087	SCV000882905	likely pathogenic	Nonsyndromic Oculocutaneous Albinism	2017-03-07	no assertion criteria provided	research