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]

Variant: NM_005633.3(SOS1):c.1490G>A (p.Arg497Gln)

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Curation History
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CA136083

45348 (ClinVar)

Gene: SOS1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 1256086f-1aff-421d-9a8c-20999b3f47d6

Approved on: 2020-07-02

Published on: 2020-07-02

HGVS expressions

NM_005633.3:c.1490G>A

NM_005633.3(SOS1):c.1490G>A (p.Arg497Gln)

NC_000002.12:g.39022938C>T

CM000664.2:g.39022938C>T

NC_000002.11:g.39250079C>T

CM000664.1:g.39250079C>T

NC_000002.10:g.39103583C>T

NG_007530.1:g.102526G>A

ENST00000395038.6:c.1490G>A

ENST00000402219.6:c.1490G>A

ENST00000426016.5:c.1490G>A

ENST00000472480.1:n.334G>A

Likely Benign

BS3 BP5

PM2 PM1 PS4 PP2 PP3

Evidence Links 1

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1490G>A (p.Arg497Gln) variant in SOS1 was present in 0.0113% (4/35392) of Latino chromosomes in gnomAD (BS1 not met; gnomad.broadinstitute.org). It has been observed in 1 proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980). Of note, it has also been observed in other probands with disparate phenotypes and their reportedly unaffected parents; however, these individuals were not well-phenotyped and, therefore, do not meet current requirements for BS2 (BS2 not met; PMID:21387466, Otto von Guericke University Magdeburg, GeneDx, Partners Laboratory for Molecular Medicine, Integrated Genetics, and Baylor Genetics internal data; ClinVar SCV000209114.12, SCV000062197.7, SCV001361139.1). In vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980). Although this variant occurs in a location defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1, expert judgement was used to classify this variant as likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): BS3, BP5.

BS3

In vitro functional studies provide some evidence that this variant does not impact protein function (BS3; PMID: 20683980).

Longoni et al. also showed that this variant did not induce ERK1 phosphorylation above the level of WT. PubMed:20683980

BP5

Observed in 1 proband with Noonan syndrome with an alternate molecular basis for disease (BP5; PMID: 20683980).

PubMed:20683980

PM2

Present in 0.01130% (4/35392) of Latino chromosomes in gnomAD v2. In v3, present in 0.007339% (1/13626) of Latino chromosomes.

PM1

Although this variant occurs in a location defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of SOS1, expert judgement was used to classify this variant as likely benign.

PS4

Observed in multiple probands with disparate phenotypes and their reportedly unaffected parents; however, these individuals were not well-phenotyped and, therefore, do not meet current requirements for BS2 (BS2 not met; PMID:21387466, Otto von Guericke University Magdeburg, GeneDx, Partners Laboratory for Molecular Medicine, Integrated Genetics, and Baylor Genetics internal data; ClinVar SCV000209114.12, SCV000062197.7, SCV001361139.1).

PP2

Although SOS1 is a missense-constrained gene (PMID: 29493581), expert judgement was used to classify this variant as likely benign.

PP3

REVEL 0.744. Entirely conserved in UCSC database. Alamut does not predict an impact to splicing. Although computational predictors and conservation analysis suggest that this variant may impact the protein, expert judgement was used to classify this variant as likely benign.

Curation History

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