Submissions for variant NM_005633.4(SOS1):c.3322G>A (p.Asp1108Asn)

gnomAD frequency: 0.00009  dbSNP: rs199856844

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000234075	SCV001424750	likely benign	RASopathy	2020-06-25	reviewed by expert panel	curation	The c.3322G>A (p.Asp1108Asn) variant in SOS1 was present in 0.039% (10/13658 with 95% CI) of Latino alleles in gnomAD v3 (BS1). This variant has been identified in a patient with Noonan syndrome who had an alternate molecular basis for disease (BP5; SCV000966758.1; ClinVar ID: 44603). It was also identified in a homozygous state in an individual who also carried a variant in TRMT1 (BP5 not met; Baylor College of Medicine internal data). In summary, this variant meets criteria to be classified as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS1, BP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234075	SCV000288965	likely benign	RASopathy	2024-12-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000333119	SCV000330895	likely benign	not provided	2021-03-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000825457	SCV000966758	uncertain significance	not specified	2018-05-02	criteria provided, single submitter	clinical testing	The p.Asp1108Asn variant has not been previously reported in individuals with cl inical features of a RASopathy disorder, but has been reported in ClinVar (Varia tion ID: 238770). This variant has been identified in 4/33558 Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; d bSNP rs199856844). Please note that for diseases with clinical variability, redu ced penetrance, or recessive inheritance, pathogenic variants may be present at a low frequency in the general population. Computational prediction tools and co nservation analysis suggest that the p.Asp1108Asn variant may not impact the pro tein, though this information is not predictive enough to rule out pathogenicity . In summary, the clinical significance of the p.Asp1108Asn variant is uncertain . ACMG/AMP Criteria applied: BP4.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000825457	SCV002103791	uncertain significance	not specified	2022-02-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321878	SCV002606225	likely benign	Cardiovascular phenotype	2024-10-03	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.