ClinVar Genomic variation as it relates to human health

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 patient with ocular albinism in trans with a splice variant (Lee 1994), 1 Japanese patient with subclinical albinisim who was refered to clinic for severe sunburns (Kawai 2008), 3 Japanese patients with mild disease who has second variants in OCA2 (not clear whether they tested they are in cis or trans) (Suzuki 2003). Transfection of mouse melanocytes with human OCA2 Ala481Thr cDNA resulted in 70% functional activity (Sviderskaya 1997; full text not available). Variant has 4.7% frequency in European population and 20 homozygotes reported in ExAC. ClinVar classification is based on OMIM. Based on the frequency and the studies reporting this variant, it is likely to be a benign variant and lead to a subclinical phenotype at most, therefore does not meet criteria for reporting in BabySeq.

Does not cause OCA2 by itself, even when present in the homozygous state, but may result in a mild form of OCA2 when present in trans with a null or nearly null allele (Suzuki et al., 2003; Kawai et al., 2005; Wei et al., 2013); Observed more frequently in individuals with lighter iris and skin pigmentation than in controls in cohort studies (Abe et al., 2013; Eaton et al., 2015; Andersen et al., 2016); Published functional studies demonstrate that this variant retains approximately 70% of wildtype protein function (Sviderskaya et al., 1997); Reported as a common benign variant in individuals of East Asian background, and individuals homozygous for A481T were reported to have normal pigmentation for their ethnicity (Yuasa et al., 2007); This variant is associated with the following publications: (PMID: 23324268, 15942220, 20981092, 8302318, 12727022, 10905897, 17008060, 25333069, 30414346, 31077556, 34426522, 31719542, 25809079, 32901917, 23165166, 24617981, 17568986, 8980282, 12687678, 27468418)

The p.Ala481Thr variant in OCA2 was identified by research genome sequencing and shown to segregate with disease in a Pakistani kindred with autosomal recessive ocular albinism (PMID: 34476810). The variant is predicted to cause a missense change (p.Ala481Thr) that is damaging according to many in silico tools including REVEL (0.72). It has been reported in OCA2 patients of Chinese (PMID: 34707637), European (PMID: 8302318) or Japanese (PMID: 31141302) ancestry, either in homozygous form or compound-heterozygous with another variant. The phenotype of patients harboring p.Ala481Thr variants is often described as less severe and its pathogenicity is much debated in the literature. The widely-cited functional impact for this variant (70% of wild-type activity) derives from a single experiment reported more than two decades ago. In 1997, Sviderskaya et al performed complementation studies of melanocytes and melanoblasts from OCA2-null mice in which transfection of mutant p.Ala481Thr cDNAs results in only partial melanin biosynthesis and hypopigmentation compared to transfection with wildtype cDNAs (PMID: 8980282). Many studies arguing against the pathogenicity of this variant originate from a research team in Japan, where the population prevalence of p.Ala481Thr is the highest (MAF ~0.051 in gnoMADv4) and it has been seen in homozygous form in both OCA2 patients and normally-pigmented homozygous carriers (PMIDs 12687678, 12713581). Population studies in East Asia have demonstrated that the derived allele is primarily restricted to northern East Asia (PMID: PMIDs: 17568986, 27081560). It is also common among North European Finnish individuals (MAF ~0.47 in gnoMADv4). This geographic distribution combined with the genetic association of p.Ala481Thr with skin pigmentation (PMID 25809079) is consistent with convergent evolution in East Asia and Europe ((PMIDs: 17182896, 17233754, 22065085). The latest release of the gnomAD database (v4) includes many more individuals from South Asia in which the p.Ala481Thr variant is very rare (MAF~0.0009). This supports the notion that population ancestry and selection history should be considered when interpreting the prevalence of this variant and its apparent phenotype. We consider the variant likely pathogenic.

OCA2: BS1, BS2

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.

Variant summary: OCA2 c.1441G>A (p.Ala481Thr) results in a non-conservative amino acid change located in the Citrate transporter-like domain (IPR004680) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0084 in 251492 control chromosomes in the gnomAD database, including 53 homozygotes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in OCA2 causing Oculocutaneous Albinism phenotype (0.0043), strongly suggesting that the variant is benign. c.1441G>A has been reported as a common variant in East Asians and individuals with this variant may be less resistant to the stress of sunburn (Yuasa_2007). At least one publication reports experimental evidence evaluating an impact on protein function and reported the variant retained approximately 70-75% of wild-type protein function (Sviderskaya_1997). Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=4), benign/likely benign (n=5)and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with brown oculocutaneous albinism and oculocutaneous, type II albinism (MIM#203200). (I) 0106 - This gene is associated with autosomal recessive disease. A single variant has been reported in two families with dominant oculocutaneous albinism (PMID: 32741191). (I) 0115 - Variants in this gene causing oculocutaneous albininism are known to have variable expressivity (PMID: 24518832). (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (I) 0251 - This variant is heterozygous. (I) 0307 - Variant is present in gnomAD (v3) at a frequency >=0.05 in the European subpopulation (964 heterozygotes, 27 homozygotes). (SB) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated transmembrane helix within the permease P domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported as pathogenic and a VUS, but more recently as likely benign and benign (ClinVar, LOVD). The variant has been described as a polymorphism that may lower pigmentation in healthy individuals (PMID: 25809079, PMID: 31196117), but also as a pathogenic or hypomorphic allele (PMID: 31719542, PMID: 32741191). (I) 1010 - Functional evidence for this variant is inconclusive. Transfected cells demonstrated a reduction to 70% of wildtype enzyme activity (ClinVar, PMID: 8980282). (I) 1201 - Heterozygous variant detected in trans with a second likely pathogenic heterozygous variant (p.(Cys777Tyr)). (I) 1205 - This variant has been shown to be maternally inherited (LABID). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).