Submissions for variant NM_006939.4(SOS2):c.3540TCC[4] (p.Pro1183dup)

dbSNP: rs765097073

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000527284	SCV000656026	benign	Noonan syndrome 9	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001797104	SCV002038706	likely benign	not provided	2021-12-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV001813500	SCV002060676	benign	Noonan syndrome and Noonan-related syndrome	2021-04-06	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002456251	SCV002616281	benign	Cardiovascular phenotype	2022-01-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000527284	SCV002762987	benign	Noonan syndrome 9		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000527284	SCV002811971	likely benign	Noonan syndrome 9	2021-09-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235287	SCV003933865	benign	not specified	2023-05-15	criteria provided, single submitter	clinical testing	Variant summary: SOS2 c.3546_3548dupTCC (p.Pro1183dup) results in an in-frame duplication that is predicted to duplicate 1 amino acid into the encoded protein. The variant allele was found at a frequency of 0.00033 in 230798 control chromosomes (gnomAD). The observed variant frequency is approximately 132 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3546_3548dupTCC in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters have assessed this variant since 2014: two classified the variant as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign.