ClinVar Genomic variation as it relates to human health

The filtering allele frequency of the c.520C>T (p.Pro174Ser) variant in the HRAS gene is 0.115% (20/11482) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Variant summary: HRAS c.520C>T (p.Pro174Ser) results in a non-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 0.00023 in 275570 control chromosomes, predominantly at a frequency of 0.0018 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 720 fold of the estimated maximal expected allele frequency for a pathogenic variant in HRAS causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.520C>T has been reported in the literature in an individual affected with Costello Syndrome, without strong evidence for pathogenicity (Johnson_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. Three ClinVar submissions including the ClinGen RASopathy Expert Panel, an FDA recognized database cite the variant as likely benign/benign (evaluation after 2014). Based on the evidence outlined above, the variant was classified as benign.

The Pro174Ser variant in HRAS has not been reported in the literature nor previo usly identified by our laboratory. Functional studies suggest the Pro174Ser vari ant would not significantly impact HRAS signaling (Yong 2011). However, this in vitro assay may not accurately represent biological function. Computational anal yses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical signific ance of the Pro174Ser variant.

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).