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NM_002880.4(RAF1):c.781C>G (p.Pro261Ala) AND RAF1-related disorder

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Dec 18, 2023
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV004541063.2

Allele description [Variation Report for NM_002880.4(RAF1):c.781C>G (p.Pro261Ala)]

NM_002880.4(RAF1):c.781C>G (p.Pro261Ala)

Gene:
RAF1:Raf-1 proto-oncogene, serine/threonine kinase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p25.2
Genomic location:
Preferred name:
NM_002880.4(RAF1):c.781C>G (p.Pro261Ala)
HGVS:
  • NC_000003.12:g.12604189G>C
  • NG_007467.1:g.64991C>G
  • NM_001354689.3:c.781C>G
  • NM_001354690.3:c.781C>G
  • NM_001354691.3:c.538C>G
  • NM_001354692.3:c.538C>G
  • NM_001354693.3:c.682C>G
  • NM_001354694.3:c.538C>G
  • NM_001354695.3:c.439C>G
  • NM_002880.4:c.781C>GMANE SELECT
  • NP_001341618.1:p.Pro261Ala
  • NP_001341619.1:p.Pro261Ala
  • NP_001341620.1:p.Pro180Ala
  • NP_001341621.1:p.Pro180Ala
  • NP_001341622.1:p.Pro228Ala
  • NP_001341623.1:p.Pro180Ala
  • NP_001341624.1:p.Pro147Ala
  • NP_002871.1:p.Pro261Ala
  • NP_002871.1:p.Pro261Ala
  • LRG_413t1:c.781C>G
  • LRG_413t2:c.781C>G
  • LRG_413:g.64991C>G
  • LRG_413p1:p.Pro261Ala
  • LRG_413p2:p.Pro261Ala
  • NC_000003.11:g.12645688G>C
  • NM_002880.3:c.781C>G
  • NR_148940.3:n.1112C>G
  • NR_148941.3:n.1112C>G
  • NR_148942.3:n.1112C>G
  • P04049:p.Pro261Ala
  • c.781C>G
Protein change:
P147A
Links:
UniProtKB: P04049#VAR_037812; dbSNP: rs121434594
NCBI 1000 Genomes Browser:
rs121434594
Molecular consequence:
  • NM_001354689.3:c.781C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.781C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.538C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.538C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.682C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.538C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.439C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.781C>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1112C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1112C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1112C>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
RAF1-related disorder
Synonyms:
RAF1-related disorders; RAF1-related condition
Identifiers:

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004764008PreventionGenetics, part of Exact Sciences
no assertion criteria provided
Pathogenic
(Dec 18, 2023) 		germlineclinical testing

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From PreventionGenetics, part of Exact Sciences, SCV004764008.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The RAF1 c.781C>G variant is predicted to result in the amino acid substitution p.Pro261Ala. This variant has been reported in multiple individuals with Noonan syndrome (see for example - Razzaque et al. 2007. PubMed ID: 17603482; Maher et al. 2018. PubMed ID: 30355600; Table S2, Leach et al. 2018. PubMed ID: 29907801). Functional studies found this variant leads to increased RAF1 kinase, consistent with a gain-of-function mechanism (Razzaque et al. 2007. PubMed ID: 17603482). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Additionally, alternate missense variants affecting this amino acid (p.Pro261Thr, p.Pro261Ser, p.Pro261His, p.Pro261Arg, p.Pro261Leu) have been reported as pathogenic (Human Gene Mutation Database). This variant is interpreted as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024