Submissions for variant NM_005633.4(SOS1):c.1310T>C (p.Ile437Thr)

dbSNP: rs397517150

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000038516	SCV000062194	pathogenic	Noonan syndrome	2014-05-12	criteria provided, single submitter	clinical testing	The p.Ile437Thr variant in SOS1 has been reported in two individuals with clinic al features of Noonan syndrome and was determined to have occurred de novo in on e of them (Lepri 2011). In addition, this variant has been identified by our lab oratory in >5 individuals with clinical features of Noonan syndrome and segregat ed with disease in 4 affected relatives from 2 families (LMM data). This variant was absent from large population studies. In summary, this variant meets criter ia to be classified as pathogenic for Noonan syndrome in an autosomal dominant m anner.
GeneDx	RCV000159164	SCV000209109	pathogenic	not provided	2022-04-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 24803665, 30541462, 30039904, 24451042, 21387466, 33042901, 20648242, 29493581, 17143282, 12628188, 31785789)
Invitae	RCV000474085	SCV000553267	pathogenic	RASopathy	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 437 of the SOS1 protein (p.Ile437Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 21387466, 24451042). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 45345). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000159164	SCV000704591	pathogenic	not provided	2016-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000474085	SCV000918268	pathogenic	RASopathy	2023-11-13	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.1310T>C (p.Ile437Thr) results in a non-conservative amino acid change located in the plekstrin homology domain of 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 250826 control chromosomes.The variant was absent in 245614 control chromosomes (gnomAD). The variant, c.1310T>C, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions, and in at least one case was reported as a de novo mutation (Lepri_2011, Prasad_2018). Additionally, a different variant at the same codon has been classified as pathogenic/likely pathogenic in ClinVar (p.Ile437Ser). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21387466, 22585553, 30039904). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Blueprint Genetics	RCV000159164	SCV000927234	pathogenic	not provided	2017-04-20	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000159164	SCV001447359	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813354	SCV002060451	pathogenic	Noonan syndrome and Noonan-related syndrome	2021-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002381310	SCV002693616	pathogenic	Cardiovascular phenotype	2021-05-25	criteria provided, single submitter	clinical testing	The p.I437T pathogenic mutation (also known as c.1310T>C), located in coding exon 10 of the SOS1 gene, results from a T to C substitution at nucleotide position 1310. The isoleucine at codon 437 is replaced by threonine, an amino acid with similar properties, and is located in the pleckstrin homology domain. This mutation has been detected in several unrelated individuals reported to have Noonan syndrome, including de novo occurrences in affected index cases (Lepri F et al. Hum Mutat, 2011 Jul;32:760-72; Moniez S et al. Eur J Endocrinol, 2018 Dec;179:409-418; Prasad RM et al. Pediatr Blood Cancer, 2018 11;65:e27362; Yang L et al. BMC Med Genet, 2018 12;19:212; Ferriero K et al. Front Pediatr, 2020 Sep;8:515; Lazzaro G et al. Mol Genet Genomic Med, 2020 04;8:e1069). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV002467540	SCV002763428	likely pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224124	SCV003920498	pathogenic	Fibromatosis, gingival, 1; Noonan syndrome 4	2021-03-30	criteria provided, single submitter	clinical testing	SOS1 NM_005633.3 exon 10 p.Ile437Thr (c.1310T>C): This variant has been reported in the literature in multiple individuals with Noonan syndrome, including two cases reported to be de novo (Lepri 2011 PMID:21387466, Prasad 2018 PMID:30039904, Yang 2018 PMID:30541462). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:45345). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In summary, this variant is classified as pathogenic based on the data above.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV002467540	SCV004048180	pathogenic	Noonan syndrome 4		criteria provided, single submitter	clinical testing	The missense variant p.I437T in SOS1 (NM_005633.4) has been reported previously in individuals affected with Noonan syndrome, including an apparently de novo occurrence (Lepri et al., 2011; Lepri et al., 2014). Missense variants in the same residue (I437N) and in nearby residues (W432R, E433K, G434R, C441Y) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The p.I437T variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between isoleucine and threonine. The p.I437T missense variant is predicted to be damaging by both SIFT and PolyPhen2. The isoleucine residue at codon 437 of SOS1 is conserved in all mammalian species. The nucleotide c.1310 in SOS1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000038516	SCV000206728	pathogenic	Noonan syndrome	2013-08-23	no assertion criteria provided	clinical testing