Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_002880.3(RAF1):c.1837C>G (p.Leu613Val)

CA257066

13960 (ClinVar)

Gene: RAF1

Condition: Noonan syndrome

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: f8f03fe0-c539-40c8-ad23-64451f155a8c

HGVS expressions

NM_002880.3:c.1837C>G

NM_002880.3(RAF1):c.1837C>G (p.Leu613Val)

NM_001354689.1:c.1897C>G

NM_001354690.1:c.1837C>G

NM_001354691.1:c.1594C>G

NM_001354692.1:c.1594C>G

NM_001354693.1:c.1738C>G

NM_001354694.1:c.1654C>G

NM_001354695.1:c.1495C>G

NR_148940.1:n.2365C>G

NR_148941.1:n.2311C>G

NR_148942.1:n.2250C>G

ENST00000251849.8:c.1837C>G

ENST00000423275.5:c.*1514C>G

ENST00000432427.2:n.1474C>G

ENST00000442415.6:c.1897C>G

ENST00000471449.1:n.526C>G

NC_000003.12:g.12584624G>C

CM000665.2:g.12584624G>C

NC_000003.11:g.12626123G>C

CM000665.1:g.12626123G>C

NC_000003.10:g.12601123G>C

NG_007467.1:g.84556C>G

Pathogenic

PS3 PS2 PP2 PM2

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1837C>G (p.Leu613Val) variant in RAF1 has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2; 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). In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). 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, PM2, PS3, PS2.

PS3

In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437).

In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). PubMed:17603483

In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). PubMed:17603482

In vitro functional studies provide some evidence that the p.Leu613Val variant may impact protein function (PS3; 17603482, 17603483, 22826437). PubMed:22826437

PS2

The c.1837C>G (p.Leu613Val) variant in RAF1 has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2; PMID 17603483).

The c.1837C>G (p.Leu613Val) variant in RAF1 has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2; PMID 17603483). PubMed:17603483

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).

Approved on: 2017-04-03

Published on: 2018-12-10

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