ClinVar Genomic variation as it relates to human health

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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

This variant is associated with the following publications: (PMID: 31401120, 26635368, 22753041)

Variant summary: SPRED1 c.30C>A (p.Asn10Lys) results in a non-conservative amino acid change located in the WH1/EVH1 domain (IPR000697) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00062 in 192104 control chromosomes. The observed variant frequency is approximately 111 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 benign. c.30C>A has been reported in the literature in individuals with varying phenotypes including Noonan Syndrome-associated characteristics and Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome) (e.g. Brems_2012, Bhoj_2017, Delio_2015, Hirata_2016). These reports do not provide unequivocal conclusions about association of the variant with Neurofibromatosis Type 1-Like Syndrome (Legius Syndrome). Functional assessment of the variant determined that it does not disrupt the interaction between the SPRED1 EVH1 domain and the NF1 GAP-related domain and that its ERK suppression activity is similar to the wild-type (Hirata_2016). The following publications have been ascertained in the context of this evaluation (PMID: 27763634, 22753041, 26214305, 26635368). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

This alteration is classified as likely 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.

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).