Submissions for variant NM_005633.4(SOS1):c.1322G>A (p.Cys441Tyr)

dbSNP: rs727504295

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154314	SCV000203975	pathogenic	Noonan syndrome	2017-03-20	criteria provided, single submitter	clinical testing	The p.Cys441Tyr variant in SOS1 has been previously identified in six individual s with clinical features of Noonan syndrome, including two confirmed de novo occ urrence (Tartaglia 2007, Zenker 2007, Lepri 2011, Korean Mutation Database, LMM data). This variant has not been identified in large population studies. In summ ary, this variant meets criteria to be classified as pathogenic for autosomal do minant Noonan spectrum disorder based on presence in multiple affected individua ls including de novo occurrences.
GeneDx	RCV000159166	SCV000209111	pathogenic	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Observed in many individuals in published literature with an SOS1-related disorder (Zenker et al., 2007; Pierpont et al., 2010; Lepri et al., 2011; Chinton et al., 2019; Shoji et al., 2019); 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; Published functional studies demonstrate normal to increased SOS1 activity (Gureasko et al., 2010, Smith et al., 2013); This variant is associated with the following publications: (PMID: 17143282, 24803665, 30417923, 31292302, 31560489, 19077116, 23487764, 17586837, 20186801, 12628188, 21387466, 29493581, 20648242, 34643321, 20133692)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534974	SCV000659127	pathogenic	RASopathy	2025-04-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SOS1 function (PMID: 20133692, 23487764). 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. ClinVar contains an entry for this variant (Variation ID: 40673). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 17586837, 19077116, 20186801, 21387466, 19020799,17143282). 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 cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 441 of the SOS1 protein (p.Cys441Tyr).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000159166	SCV001477572	pathogenic	not provided	2019-11-19	criteria provided, single submitter	clinical testing	The SOS1 c.1322G>A; p.Cys441Tyr variant (rs727504295) is reported in the literature in multiple individuals affected with Noonan syndrome (Bessis 2019, Ko 2008, Lepri 2011, Pierpont 2010, Tartaglia 2007, Zenker 2007). In at least one affected individual, the variant was not observed in either parent, suggesting a de novo origin (Tartaglia 2007). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at amino acid 441 is highly conserved, and while functional studies indicate wildtype activation of pERK (Smith 2013), the variant also exhibits increased PIP2-dependent nucleotide exchange rates (Gureasko 2010). Additionally, other amino acid substitutions at nearby codons (p.Glu433Lys, p.Gly434Arg, p.Ile437Thr) have been reported in individuals with Noonan syndrome and are considered disease-causing (Lepri 2011, Tartaglia 2007, Zenker 2007), suggesting this region is functionally important. Based on available information, the p.Cys441Tyr variant is considered to be pathogenic. References: Bessis et al. Dermatological manifestations in Noonan syndrome: a prospective multicentric study of 129 patients positive for mutation. Br J Dermatol. 2019 Jun;180(6):1438-1448. Gureasko J et al. Role of the histone domain in the autoinhibition and activation of the Ras activator Son of Sevenless. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3430-5. Ko JM et al. PTPN11, SOS1, KRAS, and RAF1 gene analysis, and genotype-phenotype correlation in Korean patients with Noonan syndrome. J Hum Genet. 2008;53(11-12):999-1006. Lepri F et al. SOS1 mutations in Noonan syndrome: molecular spectrum, structural insights on pathogenic effects, and genotype-phenotype correlations. Hum Mutat. 2011 Jul;32(7):760-72. Pierpont EI et al. Effects of germline mutations in the Ras/MAPK signaling pathway on adaptive behavior: cardiofaciocutaneous syndrome and Noonan syndrome. Am J Med Genet A. 2010 Mar;152A(3):591-600. Smith et al. NMR-based functional profiling of RASopathies and oncogenic RAS mutations. Proc Natl Acad Sci U S A. 2013 Mar 19;110(12):4574-9. Tartaglia et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. 2007 Jan;39(1):75-9. Zenker M et al. SOS1 is the second most common Noonan gene but plays no major role in cardio-facio-cutaneous syndrome. J Med Genet. 2007 Oct;44(10):651-6.
Genome-Nilou Lab	RCV002467511	SCV002763425	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000159166	SCV004011146	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	SOS1: PM6:Strong, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000534974	SCV004804324	pathogenic	RASopathy	2024-01-09	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.1322G>A (p.Cys441Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251002 control chromosomes. c.1322G>A has been reported in the literature in multiple individuals affected with Noonan Syndrome including a de novo occurrence (e.g. Pierpont_2008, Ko_2008, Tartaglia_2007, Alfieri_2008, Lepri_2011, Lee_2011.). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Gureasko_2009). The following publications have been ascertained in the context of this evaluation (PMID: 19077116, 19020799, 17143282, 19568997, 20133692, 21387466, 21784453). ClinVar contains an entry for this variant (Variation ID: 40673). Based on the evidence outlined above, the variant was classified as pathogenic.