Evidence Repository - Clinical Genome Resources

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

Link to SEPIO compliant JSON-LD document

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

CA234977

40678 (ClinVar)

Gene: SOS1

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

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

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

PS2_Very Strong PS3 PP3 PP2 PM2 PM1

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

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.

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).

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). PubMed:17143282

PS3

In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID 17143285).

In vitro functional studies provide some evidence that the p.Arg552Gly variant may impact protein function (PS3; PMID 17143285). PubMed:17143285

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).

PM2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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).

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). PubMed:29493581

Approved on: 2017-04-03

Published on: 2018-12-10

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