ClinVar

Description

Variant summary: SPRED1 c.1192G>A (p.Asp398Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00043 in 251248 control chromosomes, predominantly at a frequency of 0.0029 within the Latino subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 516 fold of the estimated maximal expected allele frequency for a pathogenic variant in SPRED1 causing Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) phenotype (5.6e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1192G>A has been reported in the literature (Messiaen_2009). This report however, does not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). In in vitro cell based assays (Elk-1 reporter assays and PC12 cell line assays), the variant was found to have wild type activity. One ClinVar submitter (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.