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 label mismatch: RAF1 vs undefined
  • 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.1472C>T (p.Thr491Ile)

CA261612

21342 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 3d3d7a51-6ba9-4434-a6d9-ebf5e4b84ae4
Approved on: 2024-12-03
Published on: 2025-03-25

HGVS expressions

NM_002880.4:c.1472C>T
NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)
NC_000003.12:g.12585745G>A
CM000665.2:g.12585745G>A
NC_000003.11:g.12627244G>A
CM000665.1:g.12627244G>A
NC_000003.10:g.12602244G>A
NG_007467.1:g.83435C>T
ENST00000423275.6:c.*1137C>T
ENST00000432427.3:c.789C>T
ENST00000460610.2:n.5217C>T
ENST00000471449.2:n.282C>T
ENST00000475353.2:n.3185C>T
ENST00000684903.1:c.*1149C>T
ENST00000685348.1:c.*1095-339C>T
ENST00000685437.1:c.1373C>T
ENST00000685653.1:c.1472C>T
ENST00000685697.1:n.2207C>T
ENST00000685738.1:c.*436C>T
ENST00000686409.1:n.4314C>T
ENST00000686455.1:n.3626C>T
ENST00000686762.1:c.*31C>T
ENST00000687257.1:n.3499C>T
ENST00000687326.1:c.*2197C>T
ENST00000687505.1:n.1590C>T
ENST00000687923.1:c.1361C>T
ENST00000688269.1:n.2068C>T
ENST00000688444.1:n.3589C>T
ENST00000688543.1:c.1373C>T
ENST00000688625.1:c.*2841C>T
ENST00000688803.1:n.2965-492C>T
ENST00000688914.1:n.458C>T
ENST00000689097.1:c.*1149C>T
ENST00000689389.1:c.1295C>T
ENST00000689418.1:c.*2940C>T
ENST00000689540.1:n.3413C>T
ENST00000689876.1:c.1418-339C>T
ENST00000689914.1:c.*406C>T
ENST00000690397.1:c.1361C>T
ENST00000690460.1:c.1460C>T
ENST00000690585.1:c.263-492C>T
ENST00000690625.1:n.2508C>T
ENST00000691396.1:c.*1344C>T
ENST00000691643.1:n.2098C>T
ENST00000691724.1:c.*429C>T
ENST00000691779.1:c.*1050C>T
ENST00000691888.1:c.346C>T
ENST00000691899.1:c.1472C>T
ENST00000692069.1:n.3829C>T
ENST00000692093.1:c.1373C>T
ENST00000692311.1:n.2296C>T
ENST00000692558.1:n.3628C>T
ENST00000692773.1:c.*1209C>T
ENST00000692830.1:c.*1217C>T
ENST00000693312.1:c.1247C>T
ENST00000693664.1:c.1488-492C>T
ENST00000693705.1:c.*1048-764C>T
ENST00000251849.9:c.1472C>T
ENST00000442415.7:c.1532C>T
ENST00000676541.1:c.*3492G>A
ENST00000677142.1:c.*3492G>A
ENST00000677816.1:c.*2047G>A
ENST00000677941.1:n.3555G>A
ENST00000251849.8:c.1472C>T
ENST00000423275.5:c.*1149C>T
ENST00000432427.2:c.1109C>T
ENST00000442415.6:c.1532C>T
ENST00000471449.1:n.161C>T
NM_002880.3:c.1472C>T
NM_001354689.1:c.1532C>T
NM_001354690.1:c.1472C>T
NM_001354691.1:c.1229C>T
NM_001354692.1:c.1229C>T
NM_001354693.1:c.1373C>T
NM_001354694.1:c.1289C>T
NM_001354695.1:c.1130C>T
NR_148940.1:n.2000C>T
NR_148941.1:n.1946C>T
NR_148942.1:n.1885C>T
NM_001354689.3:c.1532C>T
NM_001354690.2:c.1472C>T
NM_001354691.2:c.1229C>T
NM_001354692.2:c.1229C>T
NM_001354693.2:c.1373C>T
NM_001354694.2:c.1289C>T
NM_001354695.2:c.1130C>T
NR_148940.2:n.1916C>T
NR_148941.2:n.1862C>T
NR_148942.2:n.1801C>T
NM_001354690.3:c.1472C>T
NM_001354691.3:c.1229C>T
NM_001354692.3:c.1229C>T
NM_001354693.3:c.1373C>T
NM_001354694.3:c.1289C>T
NM_001354695.3:c.1130C>T
NR_148940.3:n.1916C>T
NR_148941.3:n.1862C>T
NR_148942.3:n.1801C>T
More

Pathogenic

Met criteria codes 6
PM2_Supporting PP3 PS3_Moderate PM1 PS2 PS4

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAF1 Version 2.3.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1472C>T (p.Thr491Ile variant in the RAF1 gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 491. This variant is absent from gnomAD v2 (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the RAF1 protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3_Moderate; PMID:20679480). 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 RAF1 (PM1; PMID 29493581). The variant has also been identified as a de novo occurrence with confirmed parental relationships in an individual with features of RASopathy (PS2), and the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PS3_Moderate, PP3, PM2_Supporting. (Specification Version 2.3, 12/3/2024)
Met criteria codes
PM2_Supporting
This variant is absent from gnomAD v4
PP3
Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the protein (PP3).
PS3_Moderate
In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3; 20679480).
In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3; 20679480). PubMed:20679480
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 RAF1 (PM1; PMID 29493581).
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 RAF1 (PM1; PMID 29493581). PubMed:29493581
PS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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