rs766715445

Description

The FREM2 p.Pro2837Ser variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs766715445) and in ClinVar (classified as a VUS by Illumina Clinical Services Laboratories for Cryptophthalmos syndrome). The variant was also found in 34 of 282696 chromosomes at a frequency of 0.00012 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 29 of 10364 chromosomes (freq: 0.002798), African in 1 of 24964 chromosomes (freq: 0.00004), Latino in 1 of 35436 chromosomes (freq: 0.000028) and European (non-Finnish) in 3 of 129030 chromosomes (freq: 0.000023); it was not observed in the East Asian, European (Finnish), Other and South Asian populations. 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. The p.Pro2837 residue is conserved in mammals and 4 of 5 computational analyses (PolyPhen-2, SIFT, BLOSUM, MutationTaster) suggest that the variant may impact the protein. 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.

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.