Submissions for variant NM_005633.4(SOS1):c.127G>C (p.Asp43His)

gnomAD frequency: 0.00001  dbSNP: rs730881052

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159184	SCV000209130	uncertain significance	not provided	2012-01-06	criteria provided, single submitter	clinical testing	The D43H missense substitution has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The D43H missense change is a non-conservative amino acid substitution with a negatively charged residue (Asp) being replaced by a positively charged residue (His). The position at which this substitution occurs is conserved in the protein across species. To date, there have been no disease-associated mutations reported before codon Phenylalanine 78 in SOS1. The vast majority of missense changes in SOS1 are pathogenic; however, a small number of missense polymorphisms have been identified in this gene. The variant is found in NOONAN panel(s).
Blueprint Genetics	RCV000159184	SCV000927507	uncertain significance	not provided	2018-01-04	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467502	SCV002763612	uncertain significance	Noonan syndrome 4		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002467501	SCV002763613	uncertain significance	Fibromatosis, gingival, 1		criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003162289	SCV003855944	uncertain significance	Cardiovascular phenotype	2022-11-27	criteria provided, single submitter	clinical testing	The p.D43H variant (also known as c.127G>C), located in coding exon 2 of the SOS1 gene, results from a G to C substitution at nucleotide position 127. The aspartic acid at codon 43 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003654181	SCV004533349	uncertain significance	RASopathy	2022-11-20	criteria provided, single submitter	clinical testing	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. 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) performed at Invitae indicates that this missense variant is expected to disrupt SOS1 protein function. ClinVar contains an entry for this variant (Variation ID: 40642). This variant has not been reported in the literature in individuals affected with SOS1-related conditions. This variant is present in population databases (rs730881052, gnomAD 0.002%). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 43 of the SOS1 protein (p.Asp43His).