ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.3347-1G>A (rs141565234)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000154847 SCV000204529 uncertain significance not specified 2013-12-02 criteria provided, single submitter clinical testing The 3347-1G>A variant in SOS1 has not been previously reported in individuals wi th clinical features of a Noonan spectrum disorder, but has been identified in 0 .03% (3/8600) of European American chromosomes by the NHLBI Exome Sequencing Pro ject (; dbSNP rs141565234). The 3347-1G>A varia nt occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is expected to cause altered splicing leading to an abnormal or absent protein. However, loss-of-function variants in SOS1 are not thought to be causative of N oonan spectrum disorders. Additional is needed to fully assess the clinical sign ificance of the 3347-1G>A variant.
GeneDx RCV000680312 SCV000209084 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing The c.3347-1 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.3347-1 G>A variant is observed in 30/125866 (0.0238%) alleles from individuals of non-Finnish European background in the ExAC dataset (Lek et al., 2016). This splice site variant destroys the canonical splice acceptor site in intron 20. In the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. This splice variant may lead to abnormal gene splicing or result in an abnormal message that is subject to nonsense-mediated mRNA decay. No other splice site or loss-of-function mutations in SOS1 have been reported to date in association with a Noonan spectrum disorder. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or a rare benign variant.
Invitae RCV000536574 SCV000659147 uncertain significance Rasopathy 2019-11-14 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 20 of the SOS1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs141565234, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual with suspected Noonan syndrome (PMID: 26918529). ClinVar contains an entry for this variant (Variation ID: 40726). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in SOS1 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000154847 SCV000920258 uncertain significance not specified 2018-11-19 criteria provided, single submitter clinical testing Variant summary: SOS1 c.3347-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' acceptor site. Four predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 276096 control chromosomes (gnomAD and Justino_2014). The observed variant frequency is approximately 4.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), suggesting that the variant might be benign. The variant, c.3347-1G>A, has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions as a VUS (Justino_2014, Hakami_2016). These reports 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Activating (gain of function) mutations in the SOS1 gene, which participates in the RAS-MAPK pathway, have been reported in patients with Noonan syndrome. This splice-site variant is not consistent with the spectrum of SOS1 mutations (exclusively missense changes and small in-frame deletions reported) in patients with Noonan syndrome (Lepri et al, Human Mutation, 2011). Taken together, this variant is classified as VUS-possibly benign, until more functional data become available.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106330 SCV000143828 not provided Noonan syndrome 4 no assertion provided not provided

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