Submissions for variant NM_005633.4(SOS1):c.925G>T (p.Asp309Tyr)

dbSNP: rs397517180

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038575	SCV000062253	pathogenic	Noonan syndrome	2017-03-20	criteria provided, single submitter	clinical testing	The Asp309Tyr variant in SOS1 has been identified in at least 5 individuals with the clinical features of Noonan syndrome, occurred de novo in one of these indi viduals, and segregated with phenotypic features in 2 family members of one fami ly (Narumi 2008, Roberts 2007, Zenker 2007, LMM data). This variant has been ide ntified in large population studies. In addition, functional studies showed that this variant caused an increased EGF-evoked ERK activation, which is similar to PTPN11 disease-causing variants (Roberts 2007). In summary, this variant meets criteria to be classified as pathogenic for Noonan syndrome in an autosomal domi nant manner based upon de novo occurrence, segregation studies, extremely low al lele frequency in the general population, and supporting functional evidence.
GeneDx	RCV000255002	SCV000322037	pathogenic	not provided	2018-12-27	criteria provided, single submitter	clinical testing	The D309Y variant has been published previously in association with Noonan syndrome, including an instance of de novo inheritance (Roberts et al., 2007; Zenker et al., 2007; Ezquieta et al., 2012). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. D309Y is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro studies have shown D309Y results in increased activation of ERK and RAS (Roberts et al., 2007). Additionally, the SOS1 gene has a low rate of benign missense variation and missense variants are a common mechanism of disease in this gene. Therefore, this variant is pathogenic.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813362	SCV002060452	pathogenic	Noonan syndrome and Noonan-related syndrome	2018-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV001852808	SCV002240389	pathogenic	RASopathy	2021-05-21	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with Noonan syndrome (PMID: 17143285, 18651097, 17586837). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 45379). For these reasons, this variant has been classified as Pathogenic. 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 SOS1 protein function. This variant is not present in population databases (ExAC no frequency). This sequence change replaces aspartic acid with tyrosine at codon 309 of the SOS1 protein (p.Asp309Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Experimental studies have shown that this variant affects SOS1 protein function (PMID: 17143285).
DASA	RCV002255093	SCV002526411	pathogenic	Noonan syndrome 4	2022-06-10	criteria provided, single submitter	clinical testing	The c.925G>T;p.(Asp309Tyr) missense change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 45379; PMID: 17143285; 17586837; 18651097) - PS4.Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 17143285) - PS3_supporting. This variant is not present in population databases:rs397517180 , gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The variant was assumed de novo, but without confirmation of paternity and maternity (PMID: 17143285; 17586837)PM6. The variant co-segregated with disease in multiple affected family members (PMID: 18651097) - PP1. In summary, the currently available evidence indicates that the variant is Pathogenic
Genome-Nilou Lab	RCV002255093	SCV002763482	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002255093	SCV002768755	pathogenic	Noonan syndrome 4	2020-05-25	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an aspartic acid to a tyrosine (exon 7). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif (DH-PH domain; PMID:17143285). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. Variant identified in multiple individuals with Noonan syndrome (ClinVar, PMID: 17143285; 18651097). (P) 0903 - Low evidence for segregation with disease. Three individuals with Noonan syndrome over three generations (PMID: 18651097). (P) 1002 - Moderate functional evidence supporting abnormal protein function. This variant was shown to increase ERK activation compared to wild-type in transfected cells (PMID: 17143285). (P) 1101 - Very strong and specific phenotype match. (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign