Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_006939.4(SOS2):c.800T>A (p.Met267Lys)

CA204984

209092 (ClinVar)

Gene: SOS2
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 50413a95-4bb5-4541-8121-2efb05178517
Approved on: 2024-09-17
Published on: 2024-10-01

HGVS expressions

NM_006939.4:c.800T>A
NM_006939.4(SOS2):c.800T>A (p.Met267Lys)
NC_000014.9:g.50182521A>T
CM000676.2:g.50182521A>T
NC_000014.8:g.50649239A>T
CM000676.1:g.50649239A>T
NC_000014.7:g.49718989A>T
NG_051073.1:g.54173T>A
ENST00000216373.10:c.800T>A
ENST00000216373.9:c.800T>A
ENST00000543680.5:c.800T>A
ENST00000556469.5:n.567T>A
NM_006939.2:c.800T>A
NM_006939.3:c.800T>A
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS2 PP3 PS4_Moderate

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for SOS2 Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.800T>A variant in SOS2 (NM_006939.4(SOS2):c.800T>A (p.Met267Lys)) is a missense variant predicted to cause substitution of methionine by lysine at amino acid 267. It has been identified in at least 3 probands with clinical features of a RASopathy (PS4_Moderate; SCV001426180.1, PMIDs: 25795793, 30707178). Two of these cases were reported as de novo occurrences, one with maternity and paternity confirmation and the other without (PS2, PM6; SCV001426180.1, PMID: 25795793). The computational predictor REVEL gives a score of 0.802, which is above the threshold of 0.7, evidence that correlates with impact to SOS2 function (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied: PS2, PS4_Moderate, PM2_Supporting, PP3 (Version 2.1; 9/7/2024)
Met criteria codes
PM2_Supporting
Absent from gnomAD v2 and v3
PS2
This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual, both with Noonan Syndrome (PS2; Otto von Guericke University Magdeburg Internal Data & PMID:25795793; 3 PS2 points).
PP3
The computational predictor REVEL gives a score of 0.802, which is above the threshold of 0.7, evidence that correlates with impact to SOS2 function (PP3).
PS4_Moderate
This variant has been reported in 3 probands with Noonan Syndrome (PS4_moderate; PMIDs: 25795793, 30707178 & Otto von Guericke University Magdeburg Internal Data; 3 PS4 points).
Curation History
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