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]

Variant: NM_001354689.3(RAF1):c.1931C>G (p.Ser644Cys)

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Curation History
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CA16604447

391813 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 67b91de1-64dc-44d7-9bed-c71a807398ea

Approved on: 2020-07-23

Published on: 2020-07-27

HGVS expressions

NM_001354689.3:c.1931C>G

NM_001354689.3(RAF1):c.1931C>G (p.Ser644Cys)

NM_002880.3:c.1871C>G

NM_001354689.1:c.1931C>G

NM_001354690.1:c.1871C>G

NM_001354691.1:c.1628C>G

NM_001354692.1:c.1628C>G

NM_001354693.1:c.1772C>G

NM_001354694.1:c.1688C>G

NM_001354695.1:c.1529C>G

NR_148940.1:n.2399C>G

NR_148941.1:n.2345C>G

NR_148942.1:n.2284C>G

NM_001354690.2:c.1871C>G

NM_001354691.2:c.1628C>G

NM_001354692.2:c.1628C>G

NM_001354693.2:c.1772C>G

NM_001354694.2:c.1688C>G

NM_001354695.2:c.1529C>G

NR_148940.2:n.2315C>G

NR_148941.2:n.2261C>G

NR_148942.2:n.2200C>G

ENST00000251849.8:c.1871C>G

ENST00000423275.5:c.*1548C>G

ENST00000432427.2:n.1508C>G

ENST00000442415.6:c.1931C>G

ENST00000471449.1:n.560C>G

NC_000003.12:g.12584590G>C

CM000665.2:g.12584590G>C

NC_000003.11:g.12626089G>C

CM000665.1:g.12626089G>C

NC_000003.10:g.12601089G>C

NG_007467.1:g.84590C>G

Uncertain Significance

PP2 PM1 PM2

BS2 PP3

Evidence Links 0

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1871C>G (p.Ser624Cys) variant in RAF1 was absent from large population studies (PM2; gnomad.broadinstitute.org). It has been identified in at least 1 unaffected parent of a proband with features of a RASopathy; however, this evidence does not meet current scoring criteria for BS2 (BS2 not met; GeneDx internal data, ClinVar SCV000534967.4). RAF1 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). 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). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2.

PP2

The RASopathy EP has defined RAF1 to be a missense-constrained gene where pathogenic missense variants are common (PMID: 29493581).

PM1

The RASopathy EP has defined exon 17 to be a region supporting pathogenicity (PMID: 29493581).

PM2

Absent from both versions of gnomAD.

BS2

Observed in 1 unaffected parent of a proband with features of a RASopathy (BS2 not met; GeneDx internal data, ClinVar SCV000534967.4).

PP3

REVEL 0.542, entirely conserved in UCSC database, not predicted to impact splicing.

Curation History

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