ClinVar Genomic variation as it relates to human health

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: SUOX c.228G>T (p.Arg76Ser) results in a non-conservative amino acid change in the encoded protein sequence and is within the exonic splice region. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.001 in 250708 control chromosomes, predominantly at a frequency of 0.0012 within the Latino subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1 fold of the estimated maximal expected allele frequency for a pathogenic variant in SUOX causing Sulfite Oxidase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.228G>T in individuals affected with Sulfite Oxidase Deficiency has been reported. At least one publication reports experimental evidence evaluating an impact on splicing, suggesting the variant resulted in reduced normal transcript at about 39% of WT and the exon-skipped transcript was significantly enhanced by RT-PCR in HEK293T cells, however such data conflict with the subsequent presentation in the same paper, which does not allow convincing conclusions about the variant effect (Bastarache_2018). The following publication have been ascertained in the context of this evaluation (PMID: 29590070). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (Pathogenic, n=1; Uncertain significance, n=1; Benign, n=2). Based on the evidence outlined above, the variant was classified as likely 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).