The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

  • See Evidence submitted by expert panel for details.

Variant: NM_005633.3(SOS1):c.1654A>G (p.Arg552Gly)

CA235350

12871 (ClinVar)

Gene: SOS1
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: b5a21ed5-8cbc-465c-8a14-9be1d1d54011

HGVS expressions

NM_005633.3:c.1654A>G
NM_005633.3(SOS1):c.1654A>G (p.Arg552Gly)
ENST00000395038.6:c.1654A>G
ENST00000402219.6:c.1654A>G
ENST00000426016.5:c.1654A>G
NC_000002.12:g.39022774T>C
CM000664.2:g.39022774T>C
NC_000002.11:g.39249915T>C
CM000664.1:g.39249915T>C
NC_000002.10:g.39103419T>C
NG_007530.1:g.102690A>G

Pathogenic

Met criteria codes 6
PS3 PP3 PP2 PS2_Very Strong PM1 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1654A>G (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). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID: 17143282). 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.Arg552Gly 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
PS3
In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID: 17143282).
PP3
Computational prediction tools and conservation analysis suggest that the p.Arg552Gly 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).
PS2_Very Strong
The c.1654A>G (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).
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
Approved on: 2017-04-03
Published on: 2018-12-10
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