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 sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 256 of the FAM126A protein (p.Ala256Pro). This variant is present in population databases (rs142984808, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with FAM126A-related conditions. ClinVar contains an entry for this variant (Variation ID: 359778). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect

The FAM126A p.Ala256Pro variant was not identified in the literature but was identified in dbSNP (ID: rs142984808) and ClinVar (classified as uncertain significance by Illumina for Hypomyelination and Congenital Cataract). The variant was identified in control databases in 202 of 282202 chromosomes at a frequency of 0.0007158 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 190 of 128932 chromosomes (freq: 0.001474), Other in 3 of 7202 chromosomes (freq: 0.000417), Latino in 6 of 35358 chromosomes (freq: 0.00017), European (Finnish) in 2 of 25086 chromosomes (freq: 0.00008) and African in 1 of 24912 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Ala256 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The HYCC1 c.766G>C variant is predicted to result in the amino acid substitution p.Ala256Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too frequent for an unreported disease-causing variant. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.