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

CA134687

40613 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

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

Approved on: 2017-04-03

Published on: 2018-12-10

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

• Met criteria codes: PM6_Strong PS4_Moderate PP3 PP2 PM2

Expert Panel

RASopathy VCEP

Criteria Specification Information

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.

Met criteria codes

• PM6_Strong: 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).
• 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)
• PM2: This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).