ClinVar Genomic variation as it relates to human health

Variant summary: SOS1 c.3269C>T (p.Pro1090Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 251006 control chromosomes, predominantly at a frequency of 0.00039 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c c.3269C>T has been reported in the literature in a 4 m/o patient who presented with GERD, chylous pleural effusion, chronic lung disease and astigmatism (Bhoj_2016). The final diagnosis of the patient is reported as "undiagnosed" with a variant classification as "likely benign" and a "negative" diagnosis (Bhoj_2016). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 27763634). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5) and VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.

Variant classified as Uncertain Significance - Favor Benign. The p.Pro1090Leu va riant in SOS1 has not been previously reported in individuals with a RASopathy, but has been identified in 11/66720 European chromosomes including one homozygou s individual and 6/16512 South Asian chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs730881034). Computational pr ediction tools and conservation analysis do not provide strong support for or ag ainst an impact to the protein. In summary, while the clinical significance of the p.Pro1090Leu variant is uncertain, its frequency suggests that it is more li kely to be benign.

Reported as likely benign in an individual with gastroesophageal reflux disease, chylous pleural effusion, chronic lung disease, and astigmatism. No segregation information was provided (Bhoj et al., 2017).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27763634)

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

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 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.