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.806T>C (p.Met269Thr)

Curation History

CA235344

40662 (ClinVar)

Gene: SOS1

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 4536a40e-a4fc-474b-b83d-f63fa7e74a4a

Approved on: 2017-04-03

Published on: 2018-12-10

HGVS expressions

NM_005633.3:c.806T>C

NM_005633.3(SOS1):c.806T>C (p.Met269Thr)

NC_000002.12:g.39051202A>G

CM000664.2:g.39051202A>G

NC_000002.11:g.39278343A>G

CM000664.1:g.39278343A>G

NC_000002.10:g.39131847A>G

NG_007530.1:g.74262T>C

ENST00000395038.6:c.806T>C

ENST00000402219.6:c.806T>C

ENST00000426016.5:c.806T>C

ENST00000461545.1:n.156T>C

Pathogenic

PS2_Very Strong PM2 PM1 PP3 PP2

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.806T>C (p.Met269Thr) variant in SOS1 has been reported in the literature in at least 2 unconfirmed and 1 confirmed de novo occurrences in patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 17586837; 19953625, 20683980). It has also been reported as a confirmed de novo occurrence in a patient with clinical features of a RASoapthy (PMID: 20683980). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3). 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). 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, PS2_VeryStrong.

PS2_Very Strong

PM2

This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).

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).

PP3

Computational prediction tools and conservation analysis suggest that the p.Met269Thr variant may impact the protein (PP3).

PP2

The variant is in SOS1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581).

Curation History

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