Submissions for variant NM_005633.4(SOS1):c.985G>A (p.Glu329Lys)

gnomAD frequency: 0.00001  dbSNP: rs756679265

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000654955	SCV000776863	uncertain significance	RASopathy	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 329 of the SOS1 protein (p.Glu329Lys). This variant is present in population databases (rs756679265, gnomAD 0.003%). 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: 543987). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SOS1 protein function. 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.
Institute of Human Genetics, University of Goettingen	RCV000991072	SCV001132606	uncertain significance	Noonan syndrome 4	2019-12-23	criteria provided, single submitter	clinical testing	Although the SOS1-Variant has a pathogenic computational verdict due to 10 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI and REVEL vs 2 benign predictions from DEOGEN2 and SIFT, is listed in gnomAD at a very low population frequency (1/251070 alleles) and located in the DH-domain of the SOS1-protein, our patient presented with symptoms of a CHARGE-Syndrome (although no pathogenic mutations in CHD7, SEMA3E, TBX1, TBX22 could be detected). At this moment there is no indication from the present literature, that this variant is pathogenic, but also vice versa there is no indication, that this variant is a mere rare polymorphism. Thus, we considered this variant to be a variant of unknown significance, with possibly benign character.
Ambry Genetics	RCV002386120	SCV002689335	uncertain significance	Cardiovascular phenotype	2021-10-26	criteria provided, single submitter	clinical testing	The c.985G>A (p.E329K) alteration is located in exon 8 (coding exon 8) of the SOS1 gene. This alteration results from a G to A substitution at nucleotide position 985, causing the glutamic acid (E) at amino acid position 329 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000991072	SCV002763471	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467973	SCV002763472	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469238	SCV002766298	uncertain significance	not specified	2022-11-28	criteria provided, single submitter	clinical testing	Variant summary: SOS1 c.985G>A (p.Glu329Lys) results in a conservative amino acid change located in the Dbl homology (DH) domain (IPR000219) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251070 control chromosomes (gnomAD). 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.985G>A in individuals affected with Noonan Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.