ClinVar Miner

Submissions for variant NM_005633.4(SOS1):c.3418T>A (p.Leu1140Ile)

gnomAD frequency: 0.00010  dbSNP: rs375550588
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000463473 SCV000553277 likely benign RASopathy 2023-12-18 criteria provided, single submitter clinical testing
Phosphorus, Inc. RCV000577966 SCV000679915 uncertain significance Noonan syndrome 4 2017-08-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000592644 SCV000709736 uncertain significance not specified 2018-03-06 criteria provided, single submitter clinical testing Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 7/121778 Europeans in gnomad-2:39214706 A / T, identified in 1 individual with possible Noonan syndrome, but classified as a VUS Lepri et al., 2011, benign by prediction tools
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000592644 SCV001363486 likely benign not specified 2024-07-02 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3418T>A (p.Leu1140Ile) results in a conservative amino acid change located in the SH3-binding motifs (Lepri_2011) of 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 0.00016 in 1589486 control chromosomes. The observed variant frequency is approximately 5.35 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome And Related Conditions phenotype (3e-05). c.3418T>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Lepri_2011, Ceyhan-Birsoy_2018, Shapiro_2017). Some of these report(s) classify the variant as a VUS and overall, do not provide unequivocal conclusions about association of the variant with Noonan Syndrome And Related Conditions. 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: 29696744, 21387466, 28870985). ClinVar contains an entry for this variant (Variation ID: 40729). Based on the evidence outlined above, the variant was classified as likely benign.
GeneDx RCV001588841 SCV001825022 likely benign not provided 2019-06-06 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21387466)
Ambry Genetics RCV002453287 SCV002614312 likely benign Cardiovascular phenotype 2023-12-04 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.

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