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.768G>T (p.Arg256Ser)

CA261625

40599 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 4f1ea3bf-fe0e-4be0-bb44-c2fbf8522598

HGVS expressions

NM_002880.3:c.768G>T
NM_002880.3(RAF1):c.768G>T (p.Arg256Ser)
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
ENST00000251849.8:c.768G>T
ENST00000416093.1:c.*346G>T
ENST00000423275.5:c.*445G>T
ENST00000432427.2:n.405G>T
ENST00000442415.6:c.768G>T
ENST00000465826.5:n.12G>T
ENST00000491290.1:n.289G>T
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

Pathogenic

Met criteria codes 5
PS3 PP3 PP2 PM1 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.768G>T (p.Arg256Ser) variant in RAF1 has been reported in the literature in 1 individual with clinical features of Noonan syndrome and one individual with clinical features of Noonan syndrome with multiple lentigines. This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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). Computational prediction tools and conservation analysis suggest that the p.Arg256Ser variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PS3; 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PS3; 20679480).
PP3
Computational prediction tools and conservation analysis suggest that the p.Arg256Ser variant may impact the protein (PP3).
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).
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)
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Approved on: 2017-04-03
Published on: 2018-12-10
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