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

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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

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 5
PM6_Strong PM2 PP3 PP2 PS4_Moderate

Evidence Links 0

Expert Panel

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.
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).
PM2
This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org).
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)
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).
Approved on: 2017-04-03
Published on: 2018-12-10
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