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.1472C>T (p.Thr491Ile)

CA261612

21342 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
UUID: 3d3d7a51-6ba9-4434-a6d9-ebf5e4b84ae4

HGVS expressions

NM_002880.3:c.1472C>T
NM_002880.3(RAF1):c.1472C>T (p.Thr491Ile)
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
ENST00000251849.8:c.1472C>T
ENST00000423275.5:c.*1149C>T
ENST00000432427.2:n.1109C>T
ENST00000442415.6:c.1532C>T
ENST00000471449.1:n.161C>T
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

Pathogenic

Met criteria codes 5
PP3 PP2 PM2 PM1 PS3

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1472C>T (p.Thr491Ile) variant in RAF1 has been reported in the literature in at least one individual with clinical features of a RASopathy (PS4 not met; PMID 17603483). 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.Thr491Ile variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile 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
PP3
Computational prediction tools and conservation analysis suggest that the p.Thr491Ile 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).
PM2
This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).
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).

PS3
In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3; 20679480).

Approved on: 2017-04-03
Published on: 2018-12-10
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