ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 25691160, 16518851, 19047918, 19966803, 23334668, 28098151, 28594414, 26918529, 29146900)

Variant summary: NRAS c.34G>A (p.Gly12Ser) results in a non-conservative amino acid change located in the Small GTP-binding protein domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251484 control chromosomes (gnomAD). c.34G>A has been reported in the literature in neonates affected with cystic hygroma (example: Mason-Suares_NRAS_EJHG_2017) and an individual affected with Noonan Syndrome reported as a de novo occurrence (example: Altmuller_2017). At-least one study have reported this variant affects the normal activity of the protein (example: Motoda_2007). Other variants affecting the same residue have been classified as pathogenic in ClinVar (examples: CV ID 219097, 40469, 39648, 40470). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19966803, 21263000). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NRAS protein function. ClinVar contains an entry for this variant (Variation ID: 177778). This missense change has been observed in individual(s) with clinical features of a RASopathy (PMID: 28098151, 28594414). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 12 of the NRAS protein (p.Gly12Ser).

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with NRAS-related conditions (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Noonan syndrome, caused by germline variants in the NRAS gene, have variable expressivity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2 & v3) (3 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Ras domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. Changes to cysteine, aspartic acid and arginine have been identified in individuals with germline or somatic conditions related to the NRAS gene (ClinVar), including individuals with juvenile myelomonocytic leukemia (PMID: 19047918). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals with germline or somatic conditions related to the NRAS gene. Of note, it has been reported in individuals with juvenile myelomonocytic leukemia (ClinVar, PMID: 19047918). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed) (by an external laboratory). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

The Gly12Ser variant has been identified by our laboratory in one individual wit h juvenile myelomonocytic leukemia (JMML) and dysmorphic features. In addition, this variant has been reported in 3 other individuals with JMML (Yoshida 2009), and was not identified in large population studies. Functional studies have show n the Gly12Ser variant causes constitutive NRAS signaling in the absence of grow th factor (Cirstea 2010). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly12Ser var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other variants at the Gly12 residue in RAS genes (NRAS , KRAS, HRAS) have been associated with multiple cancers, highlighting the impor tance of this position in cell signaling (Schubbert 2007). While this variant ha s not been identified in individuals with classic features of Noonan syndrome, i t is likely due to the severe impact of the variant. In summary, this variant me ets our criteria for pathogenicity for JMML and Noonan-spectrum disorders (http: //pcpgm.partners.org/LMM).