NM_005633.3:c.1867T>A

CA346365197

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: e1a27f96-c415-42ee-a544-66d4c7ee7923

HGVS expressions

NM_005633.3:c.1867T>A
NC_000002.12:g.39014838A>T
CM000664.2:g.39014838A>T
NC_000002.11:g.39241979A>T
CM000664.1:g.39241979A>T
NC_000002.10:g.39095483A>T
NG_007530.1:g.110626T>A
ENST00000395038.6:c.1867T>A
ENST00000402219.6:c.1867T>A
ENST00000426016.5:c.1867T>A

Likely Pathogenic

• Met criteria codes: PS4_Supporting PS2 PP3 PP2 PM2

• Not Met criteria codes: BS2 BS1 BS4 BS3 BP5 BP7 BP4 BP1 BP2 BP3 PS3 PS1 PP1 PM4 PM1 PM5 PM6 BA1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1867T>A (p.Phe623Ile) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of Noonan syndrome (PS2; PMID 17586837, 20673819). The p.Phe623Ile variant has also been identified in another independent occurrence in a patient with clinical features of Noonan syndrome (PS4_Supporting; PMID 20673819). This variant was absent from large population studies (PM2; gnomAD; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that the p.Phe623Ile variant may impact the protein (PP3). The variant is located in the SOS1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Of note, two different pathogenic missense variants have been previously reported at this codon of SOS1 (p.Phe623Val and p.Phe623Glu) which may indicate that this residue is critical to the function of the protein, however these variants have not yet met the criteria to be classified as pathogenic (PM5 not met). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2, PS4_Supporting, PM2, PP2, PP3.

Met criteria codes

• PS4_Supporting: 2 patients total have been described to have NS with the p.F623I variant, but one patient was counted towards PS2 for de novo. 1 separate case, therefore you can count as PS4_Supporting.
• PS2: (p.Phe623Ile) was identified in two probands with clinical features of Noonan syndrome, which occured de novo in 1 of these individuals with confirmed paternity (Zenker 2007, Fabretto 2010).
• PP3: REVEL score of 0.733 >0.7 cutoff. Some crystal structure data suggests that the residue may interact with other residues but it is not confirmed functionally.
• PP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: Variant is absent from gnomAD

Not Met criteria codes

• BS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: Variant is absent from gnomAD
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: The p.Phe623Ile variant has not been functionally assessed specifically despite the p.Phe623Glu variant having been assessed and found to impact SOS1 activity. PS3 cannot be applied.
• BP5: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP4: REVEL score of 0.733 >0.7 cutoff. Some crystal structure data suggests that the residue may interact with other residues but it is not confirmed functionally.
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: The p.Phe623Ile variant has not been functionally assessed specifically despite the p.Phe623Glu variant having been assessed and found to impact SOS1 activity. PS3 cannot be applied.
• PS1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM5: If the p.Phe623Ile variant was pathogenic it could be used for p.Phe623Val to meet PM5 as that variant is on the borderline of VUS/LP, however, the p.Phe623Val variant cannot be used as evidence to support the usage of PM5 for this variant. Additionally, the p.Phe623Glu variant will be curated separately as it has been functionally assessed by Hall 2001 11333268.
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: Variant is absent from gnomAD

Approved on: 2019-02-28

Published on: 2019-07-15