Submissions for variant NM_005633.4(SOS1):c.3391+3_3391+6del

dbSNP: rs756201866

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780751	SCV000918264	uncertain significance	not specified	2021-04-20	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.3391+3_3391+6delTAGT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5 splicing donor site. One predicts the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 250474 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3391+3_3391+6delTAGT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One other ClinVar submitter (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001244639	SCV001417873	uncertain significance	RASopathy	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 21 of the SOS1 gene. It does not directly change the encoded amino acid sequence of the SOS1 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs756201866, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 633001). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV002307614	SCV002601244	uncertain significance	not provided	2024-05-13	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV002458398	SCV002616953	uncertain significance	Cardiovascular phenotype	2021-12-17	criteria provided, single submitter	clinical testing	The c.3391+3_3391+6delTAGT intronic variant, is located 3 nucleotides after coding exon 21 of the SOS1 gene. This variant results from a deletion of 4 nucleotides at positions c.3391+3 to c.3391+6. These nucleotide positions are well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV002468042	SCV002763218	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002468041	SCV002763220	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002468042	SCV004171403	uncertain significance	Noonan syndrome 4	2023-11-13	criteria provided, single submitter	clinical testing	The SOS1 c.3391+3_3391+6del intronic change results in a deletion of four nucleotides of intron 21 of the SOS1 gene. Algorithms that predict the impact of sequence changes on splicing indicate that this change may impact splicing, but to our knowledge these predictions have not been confirmed by RNA studies. This variant has a maximum subpopulation frequency of 0.02% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). 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.