Variant: NM_005633.3(SOS1):c.1642A>C (p.Ser548Arg)

CA234977

40678 (ClinVar)

Gene: SOS1

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

UUID: 940ad8e1-71b4-424b-b085-ae78bed7e9d7

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_005633.3:c.1642A>C
NM_005633.3(SOS1):c.1642A>C (p.Ser548Arg)
ENST00000395038.6:c.1642A>C
ENST00000402219.6:c.1642A>C
ENST00000426016.5:c.1642A>C
NC_000002.12:g.39022786T>G
CM000664.2:g.39022786T>G
NC_000002.11:g.39249927T>G
CM000664.1:g.39249927T>G
NC_000002.10:g.39103431T>G
NG_007530.1:g.102678A>C

Pathogenic

• Met criteria codes: PS2_Very Strong PS3 PM1 PM2 PP3 PP2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.1642A>C (p.Ser548Arg) variant in SOS1 has been reported as a confirmed de novo occurrence in a patient with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282). In vitro functional studies provide some evidence that the p.Ser548Arg variant may impact protein function (PS3; PMID 23487764). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PP2, PP3, PM1, PM2, PS3 PS2_VeryStrong.

Met criteria codes

• PS2_Very Strong: The p.Arg552Gly variant in SOS1 has been reported as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17143282).
• PS3: In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID 17143285).
• PM1: Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1 (PM1; PMID 29493581).
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: Computational prediction tools and conservation analysis suggest that the p.Ser548Arg variant may impact the protein (PP3).
• PP2: 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).