Submissions for variant NM_005633.4(SOS1):c.2312T>C (p.Ile771Thr)

gnomAD frequency: 0.00005  dbSNP: rs557328600

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000703796	SCV000832715	likely benign	RASopathy	2024-07-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175592	SCV001339236	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.2312T>C (p.Ile771Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251082 control chromosomes (gnomAD). The observed variant frequency is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.2312T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV002442524	SCV002735350	uncertain significance	Cardiovascular phenotype	2023-04-04	criteria provided, single submitter	clinical testing	The p.I771T variant (also known as c.2312T>C), located in coding exon 14 of the SOS1 gene, results from a T to C substitution at nucleotide position 2312. The isoleucine at codon 771 is replaced by threonine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species, and threonine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002468023	SCV002763312	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468022	SCV002763313	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002468023	SCV005689313	uncertain significance	Noonan syndrome 4	2025-02-05	criteria provided, single submitter	clinical testing	The SOS1 c.2312T>C (p.Ile771Thr) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant occurs in a gene where missense variants are more likely to be damaging based on methods described by Lek et al. (PMID: 27535533). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Noonan syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003980317	SCV004792529	likely benign	SOS1-related disorder	2022-11-07	no assertion criteria provided	clinical testing	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).