Submissions for variant NM_000275.3(OCA2):c.1349C>T (p.Thr450Met)

gnomAD frequency: 0.00003  dbSNP: rs772019064

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001583207	SCV001810835	pathogenic	not provided	2023-09-06	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: 18683130, 26165494, 28976636, 31077556, 21458243, 35488210, 31196117, 18821858, 34838614)
3billion	RCV001810100	SCV002058882	likely pathogenic	Tyrosinase-positive oculocutaneous albinism	2022-01-03	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV001211398, PMID:18821858, PS1_P). A different missense change at the same codon has been reported to be associated with OCA2 related disorder (PMID:29437493,19865097, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.953, PP3_P). A missense variant is a common mechanism associated with Albinism (PP2_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000018, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV001583207	SCV002232220	pathogenic	not provided	2024-01-24	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 450 of the OCA2 protein (p.Thr450Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with oculocutaneous albinism (PMID: 26165494, 28976636, 31077556, 31813138). 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: 1211398). 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.
CeGaT Center for Human Genetics Tuebingen	RCV001583207	SCV002822167	pathogenic	not provided	2022-10-01	criteria provided, single submitter	clinical testing	OCA2: PM3:Very Strong, PM2, PM5, PP3
Laboratoire de Génétique Moléculaire, CHU Bordeaux	RCV001810100	SCV003804565	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470868	SCV004209020	pathogenic	SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES	2024-03-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003910909	SCV004735266	likely pathogenic	OCA2-related disorder	2023-10-18	criteria provided, single submitter	clinical testing	The OCA2 c.1349C>T variant is predicted to result in the amino acid substitution p.Thr450Met. This variant has been reported along with a second OCA2 variant in individuals with oculocutaneous albinism (see for example, Rooryck et al. 2008. PubMed ID: 18821858; Marti et al. 2017. PubMed ID: 28976636; Zhong et al. 2019. PubMed ID: 31077556). This variant was also described in two large cohorts of individuals affected with oculocutaneous albinism (Ma et al. 2021. PubMed ID: 34707637; Xiao et al. 2022. PubMed ID: 35488210). Additionally, alternate substitutions of this amino acid residue (p.Thr450Lys and p.Thr450Arg) have been reported in individuals with oculocutaneous albinism (Wei et al. 2010. PubMed ID: 19865097; Qiu et al. 2018. PubMed ID: 29437493). The c.1349C>T (p.Thr450Met) variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-28230225-G-A). Given the evidence, we interpret this variant as likely pathogenic.
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV001810100	SCV004806464	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2024-03-25	criteria provided, single submitter	clinical testing