Submissions for variant NM_000275.3(OCA2):c.2020C>G (p.Leu674Val)

gnomAD frequency: 0.00015  dbSNP: rs371412500

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000175395	SCV000226870	uncertain significance	not provided	2017-11-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624462	SCV000741451	pathogenic	Inborn genetic diseases	2016-04-26	criteria provided, single submitter	clinical testing
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV001078137	SCV001190097	uncertain significance	Diarrhea; Congenital nystagmus; Febrile seizure (within the age range of 3 months to 6 years); Oculocutaneous albinism; Respiratory tract infection; Motor delay, mild	2019-12-19	criteria provided, single submitter	clinical testing	The c.2020C>G variant is not present in publicly available databases like Exome Variant Server (EVS) however present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a low minor allele frequency (MAF<0.001) including one homozygote. The variant is present in our in-house exome database in heterozygous state (MAF~0.004). The variant was earlier reported to ClinVar (Accession ID: VCV000194918.1) with conflicting interpretation of pathogenicity (likely pathogenic/uncertain significance). In-silico pathogenicity prediction programs Like SIFT, PolyPhen-2, MutationTaster2, CADD etc. predicted this variant as likely deleterious, however there are no functional studies performed earlier to prove this. Due to lack of enough evidence and also considering the additional phenotypes observed in this patient along with oculocutaneous albinism and nystagmus, the variant as has been classified as uncertain significance as per ACMG guidelines.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000175395	SCV001536002	pathogenic	not provided	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 674 of the OCA2 protein (p.Leu674Val). This variant is present in population databases (rs371412500, gnomAD 0.3%). This missense change has been observed in individual(s) with clinical features of ocular albinism (PMID: 23010199, 28667292; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1948C>G. ClinVar contains an entry for this variant (Variation ID: 194918). 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 not expected to disrupt OCA2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000175395	SCV001982337	uncertain significance	not provided	2021-03-18	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in apparent homozygous state in multiple unrelated healthy adult individuals tested at GeneDx and in large population cohorts (Lek et al., 2016); Observed with an additional OCA2 variant in patients with hypomorphic albinism in the published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (also known as p.L650V using alternate nomenclature; Mondal et al., 2012; Norman et al., 2017); Observed in the apparent homozygous state in a patient with features of ocular albinism in the published literature (Mondal et al., 2012); This variant is associated with the following publications: (PMID: 23970088, 23010199, 28667292)
Revvity Omics, Revvity	RCV000175395	SCV002020185	likely pathogenic	not provided	2023-09-13	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001797661	SCV002039754	uncertain significance	Tyrosinase-positive oculocutaneous albinism	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818421	SCV002069200	uncertain significance	not specified	2018-06-15	criteria provided, single submitter	clinical testing
3billion	RCV001797661	SCV002521571	uncertain significance	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: 0.032%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.65). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OCA2 related disorder (ClinVar ID: VCV000194918 / PMID: 23010199). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as uncertain significanceaccording to the recommendation of ACMG/AMP guideline.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV001797661	SCV004021946	likely pathogenic	Tyrosinase-positive oculocutaneous albinism		criteria provided, single submitter	clinical testing