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.1193G>T (p.Arg398Leu)

CA235336

40614 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 54e513e4-3d82-4530-8f42-82522d750073
Approved on: 2024-09-17
Published on: 2024-10-01

HGVS expressions

NM_002880.4:c.1193G>T
NM_002880.4(RAF1):c.1193G>T (p.Arg398Leu)
NC_000003.12:g.12591708C>A
CM000665.2:g.12591708C>A
NC_000003.11:g.12633207C>A
CM000665.1:g.12633207C>A
NC_000003.10:g.12608207C>A
NG_007467.1:g.77472G>T
ENST00000423275.6:c.*858G>T
ENST00000432427.3:c.510G>T
ENST00000465826.6:n.784G>T
ENST00000475353.2:n.1115G>T
ENST00000491290.2:n.1553G>T
ENST00000494557.2:n.1004G>T
ENST00000684903.1:c.*870G>T
ENST00000685348.1:c.*870G>T
ENST00000685437.1:c.1094G>T
ENST00000685653.1:c.1193G>T
ENST00000685738.1:c.*157G>T
ENST00000686409.1:n.2244G>T
ENST00000686455.1:n.1556G>T
ENST00000686762.1:c.1193G>T
ENST00000687257.1:n.1429G>T
ENST00000687326.1:c.*127G>T
ENST00000687486.1:c.385G>T
ENST00000687505.1:n.1311G>T
ENST00000687923.1:c.1082G>T
ENST00000687940.1:n.1570G>T
ENST00000688269.1:n.1789G>T
ENST00000688326.1:c.626G>T
ENST00000688444.1:n.1519G>T
ENST00000688543.1:c.1094G>T
ENST00000688625.1:c.*771G>T
ENST00000688803.1:n.1424G>T
ENST00000688914.1:n.179G>T
ENST00000689097.1:c.*870G>T
ENST00000689389.1:c.1193G>T
ENST00000689418.1:c.*870G>T
ENST00000689481.1:c.*870G>T
ENST00000689540.1:n.1343G>T
ENST00000689876.1:c.1193G>T
ENST00000689914.1:c.*127G>T
ENST00000690397.1:c.1082G>T
ENST00000690460.1:c.1181G>T
ENST00000690585.1:c.85G>T
ENST00000690625.1:n.1496G>T
ENST00000691396.1:c.*1045G>T
ENST00000691724.1:c.*150G>T
ENST00000691779.1:c.*771G>T
ENST00000691888.1:c.85G>T
ENST00000691899.1:c.1193G>T
ENST00000692069.1:n.1759G>T
ENST00000692093.1:c.1094G>T
ENST00000692311.1:n.2017G>T
ENST00000692558.1:n.1558G>T
ENST00000692773.1:c.*930G>T
ENST00000692830.1:c.*938G>T
ENST00000693069.1:c.*127G>T
ENST00000693312.1:c.968G>T
ENST00000693664.1:c.1193G>T
ENST00000693705.1:c.*870G>T
ENST00000251849.9:c.1193G>T
ENST00000442415.7:c.1253G>T
ENST00000251849.8:c.1193G>T
ENST00000423275.5:c.*870G>T
ENST00000432427.2:c.830G>T
ENST00000442415.6:c.1253G>T
ENST00000460610.1:n.150G>T
ENST00000465826.5:n.550G>T
ENST00000475353.1:n.361G>T
ENST00000494557.1:n.209G>T
NM_002880.3:c.1193G>T
NM_001354689.1:c.1253G>T
NM_001354690.1:c.1193G>T
NM_001354691.1:c.950G>T
NM_001354692.1:c.950G>T
NM_001354693.1:c.1094G>T
NM_001354694.1:c.1010G>T
NM_001354695.1:c.851G>T
NR_148940.1:n.1721G>T
NR_148941.1:n.1667G>T
NR_148942.1:n.1606G>T
NM_001354689.3:c.1253G>T
NM_001354690.2:c.1193G>T
NM_001354691.2:c.950G>T
NM_001354692.2:c.950G>T
NM_001354693.2:c.1094G>T
NM_001354694.2:c.1010G>T
NM_001354695.2:c.851G>T
NR_148940.2:n.1637G>T
NR_148941.2:n.1583G>T
NR_148942.2:n.1522G>T
NM_001354690.3:c.1193G>T
NM_001354691.3:c.950G>T
NM_001354692.3:c.950G>T
NM_001354693.3:c.1094G>T
NM_001354694.3:c.1010G>T
NM_001354695.3:c.851G>T
NR_148940.3:n.1637G>T
NR_148941.3:n.1583G>T
NR_148942.3:n.1522G>T
More

Uncertain Significance

Met criteria codes 2
PP3 PM2_Supporting
Not Met criteria codes 1
PS4

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.1193G>T variant in the RAF1 gene is a missense variant predicted to cause substitution of arginine by leucine at amino acid 398 (p.Arg398Leu). This variant is absent from gnomAD v4 (PM2_Supporting). The computational predictor REVEL gives a score of 0.861, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function. The variant is also entirely conserved in the UCSC database, and Alamut does not predict an impact to splicing (PP3). This variant has been identified in at least 5 probands with variable phenotypic features, with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children's Institute for Genomic Medicine internal communications, Invitae; SCV000209025.5; SCV000207671.1; SCV000552095.2, SCV000552095.6). In summary, this variant meets criteria to be classified as a variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PM2_supporting, PP3. (Specification Version 2.1, 9/17/2024)
Met criteria codes
PP3
This variant has a REVEL score of 0.861, which is above the threshold of 0.7 and is evidence that correlates with impact to RAF1 function. The variant is entirely conserved in the UCSC database, and Alamut does not predict an impact to splicing.
PM2_Supporting
This variant is absent from gnomAD v4
Not Met criteria codes
PS4
This variant has been identified in at least 5 probands with variable phenotypic features with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children's Institute for Genomic Medicine internal communications, Invitae; SCV000209025.5; SCV000207671.1; SCV000552095.2, SCV000552095.6).
Curation History
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