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.806T>C (p.Met269Thr)

CA235344

40662 (ClinVar)

Gene: SOS1
Condition: Noonan syndrome
Inheritance Mode: Autosomal dominant inheritance
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
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Pathogenic

Met criteria codes 5
PP3 PP2 PM1 PM2 PS2_Very Strong

Evidence Links 3

Expert Panel

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.
Met criteria codes
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).
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
This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).
PS2_Very Strong
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).

Curation History
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