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.1082G>C (p.Gly361Ala)

CA134687

40613 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 04812bc6-1939-486b-9212-b10aa1e3260e

HGVS expressions

NM_002880.3:c.1082G>C

NM_002880.3(RAF1):c.1082G>C (p.Gly361Ala)

NC_000003.12:g.12599717C>G

CM000665.2:g.12599717C>G

NC_000003.11:g.12641216C>G

CM000665.1:g.12641216C>G

NC_000003.10:g.12616216C>G

NG_007467.1:g.69463G>C

NM_001354689.1:c.1142G>C

NM_001354690.1:c.1082G>C

NM_001354691.1:c.839G>C

NM_001354692.1:c.839G>C

NM_001354693.1:c.983G>C

NM_001354694.1:c.899G>C

NM_001354695.1:c.740G>C

NR_148940.1:n.1497G>C

NR_148941.1:n.1497G>C

NR_148942.1:n.1495G>C

ENST00000251849.8:c.1082G>C

ENST00000423275.5:c.*759G>C

ENST00000432427.2:n.719G>C

ENST00000442415.6:c.1142G>C

ENST00000460610.1:n.39G>C

ENST00000465826.5:n.326G>C

Pathogenic

PS4_Moderate PP3 PP2 PM6_Strong PM2

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1082G>C (p.Gly361Ala) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381 ClinVar SCV000209024.9). The p.Gly361Ala variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000209024.9, SCV000061333.5). 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.Gly361Ala variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PP2, PP3.

PS4_Moderate

The p.Gly361Ala variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Supporting; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000209024.9, SCV000061333.5).

PP3

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

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)

PM6_Strong

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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.