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]
  • See Evidence submitted by expert panel for details.

Variant: NM_002880.3(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: 2019-12-05
Published on: 2019-12-05

HGVS expressions

NM_002880.3:c.1193G>T
NM_002880.3(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_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
NM_002880.4:c.1193G>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 3
PP2 PP3 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1193G>T (p.Arg398Leu) variant has been identified in at least 4 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; SCV000209025.5; SCV000207671.1; SCV000552095.2). This variant was absent from large population studies (PM2). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common; however, it is in a region that generally lacks pathogenic variants (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg398Leu variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg398Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PP2, PP3.
Met criteria codes
PP2
The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
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