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_002880.4(RAF1):c.768G>T (p.Arg256Ser)

CA261625

40599 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4f1ea3bf-fe0e-4be0-bb44-c2fbf8522598
Approved on: 2024-09-17
Published on: 2024-10-01

HGVS expressions

NM_002880.4:c.768G>T
NM_002880.4(RAF1):c.768G>T (p.Arg256Ser)
NC_000003.12:g.12604202C>A
CM000665.2:g.12604202C>A
NC_000003.11:g.12645701C>A
CM000665.1:g.12645701C>A
NC_000003.10:g.12620701C>A
NG_007467.1:g.64978G>T
ENST00000416093.2:c.*445G>T
ENST00000423275.6:c.*445G>T
ENST00000432427.3:c.88G>T
ENST00000465826.6:n.359G>T
ENST00000491290.2:n.1145G>T
ENST00000684903.1:c.*445G>T
ENST00000685348.1:c.*445G>T
ENST00000685437.1:c.669G>T
ENST00000685653.1:c.768G>T
ENST00000685738.1:c.768G>T
ENST00000685959.1:c.768G>T
ENST00000686409.1:n.1368G>T
ENST00000686455.1:n.1131G>T
ENST00000686479.1:n.1139G>T
ENST00000686762.1:c.768G>T
ENST00000687257.1:n.1004G>T
ENST00000687326.1:c.768G>T
ENST00000687486.1:c.88G>T
ENST00000687505.1:n.886G>T
ENST00000687923.1:c.669G>T
ENST00000687940.1:n.1145G>T
ENST00000688269.1:n.1376G>T
ENST00000688326.1:c.88G>T
ENST00000688444.1:n.1094G>T
ENST00000688543.1:c.669G>T
ENST00000688625.1:c.*346G>T
ENST00000688803.1:n.999G>T
ENST00000689033.1:c.768G>T
ENST00000689097.1:c.*445G>T
ENST00000689389.1:c.768G>T
ENST00000689418.1:c.*445G>T
ENST00000689481.1:c.*445G>T
ENST00000689540.1:n.918G>T
ENST00000689876.1:c.768G>T
ENST00000689914.1:c.768G>T
ENST00000690397.1:c.669G>T
ENST00000690460.1:c.768G>T
ENST00000690625.1:n.1071G>T
ENST00000691268.1:c.262-3787G>T
ENST00000691396.1:c.*561G>T
ENST00000691724.1:c.768G>T
ENST00000691779.1:c.*346G>T
ENST00000691899.1:c.768G>T
ENST00000692093.1:c.669G>T
ENST00000692311.1:n.1141G>T
ENST00000692558.1:n.1133G>T
ENST00000692773.1:c.*445G>T
ENST00000692830.1:c.*513G>T
ENST00000693069.1:c.669G>T
ENST00000693312.1:c.543G>T
ENST00000693664.1:c.768G>T
ENST00000693705.1:c.*445G>T
ENST00000251849.9:c.768G>T
ENST00000442415.7:c.768G>T
ENST00000251849.8:c.768G>T
ENST00000416093.1:c.*346G>T
ENST00000423275.5:c.*445G>T
ENST00000432427.2:c.405G>T
ENST00000442415.6:c.768G>T
ENST00000465826.5:n.12G>T
ENST00000491290.1:n.289G>T
NM_002880.3:c.768G>T
NM_001354689.1:c.768G>T
NM_001354690.1:c.768G>T
NM_001354691.1:c.525G>T
NM_001354692.1:c.525G>T
NM_001354693.1:c.669G>T
NM_001354694.1:c.525G>T
NM_001354695.1:c.426G>T
NR_148940.1:n.1183G>T
NR_148941.1:n.1183G>T
NR_148942.1:n.1183G>T
NM_001354689.3:c.768G>T
NM_001354690.2:c.768G>T
NM_001354691.2:c.525G>T
NM_001354692.2:c.525G>T
NM_001354693.2:c.669G>T
NM_001354694.2:c.525G>T
NM_001354695.2:c.426G>T
NR_148940.2:n.1099G>T
NR_148941.2:n.1099G>T
NR_148942.2:n.1099G>T
NM_001354690.3:c.768G>T
NM_001354691.3:c.525G>T
NM_001354692.3:c.525G>T
NM_001354693.3:c.669G>T
NM_001354694.3:c.525G>T
NM_001354695.3:c.426G>T
NR_148940.3:n.1099G>T
NR_148941.3:n.1099G>T
NR_148942.3:n.1099G>T
More

Likely Pathogenic

Met criteria codes 4
PM2_Supporting PS3_Supporting PS4_Moderate PM1
Not Met criteria codes 2
BP4 PP3

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.768G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by serine at amino acid 256 (p.Arg256Ser). This variant is absent from gnomAD 4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.665, which does not meet PP3 or BP4. This variant is located in the CR2 critical functional domain as defined by the ClinGen RASopathy Expert Panel (PM1). This variant has been reported in 3 individuals with clinical features of Noonan syndrome (PS4_Moderate, PMIDs: 17603483, 22190897, 31292302). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PMID: 20679480). ERK phosphorylation assay showed that the p.Arg256Ser variant led to significantly increased phosphorylation compared to wild-type (PS3_Supporting; PMID:20679480). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PS3_Supporting, PM2_Supporting (Specification Version 2.1, 9/17/2024)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4
PS3_Supporting
ERK phosphorylation assay showed that the p.Arg256Ser variant led to significantly increased phosphorylation compared to wild-type (PMID 20679480)
PS4_Moderate
This variant has been reported in 3 individuals with clinical features of Noonan syndrome (PMIDs: 17603483, 22190897, 31292302)
PM1
This variant is located in the CR2 critical functional domain as defined by the ClinGen RASopathy Expert Panel
Not Met criteria codes
BP4
The computational predictor REVEL gives a score of 0.665, which does not meet BP4
PP3
The computational predictor REVEL gives a score of 0.665, which does not meet PP3
Curation History
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