NM_002880.4(RAF1):c.775T>G (p.Ser259Ala) AND RASopathy

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 25, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

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:: RCV001250388.1

Allele description [Variation Report for NM_002880.4(RAF1):c.775T>G (p.Ser259Ala)]

NM_002880.4(RAF1):c.775T>G (p.Ser259Ala)

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.775T>G (p.Ser259Ala)

HGVS:

NC_000003.12:g.12604195A>C
NG_007467.1:g.64985T>G
NM_001354689.3:c.775T>G
NM_001354690.3:c.775T>G
NM_001354691.3:c.532T>G
NM_001354692.3:c.532T>G
NM_001354693.3:c.676T>G
NM_001354694.3:c.532T>G
NM_001354695.3:c.433T>G
NM_002880.4:c.775T>GMANE SELECT
NP_001341618.1:p.Ser259Ala
NP_001341619.1:p.Ser259Ala
NP_001341620.1:p.Ser178Ala
NP_001341621.1:p.Ser178Ala
NP_001341622.1:p.Ser226Ala
NP_001341623.1:p.Ser178Ala
NP_001341624.1:p.Ser145Ala
NP_002871.1:p.Ser259Ala
NP_002871.1:p.Ser259Ala
LRG_413t1:c.775T>G
LRG_413t2:c.775T>G
LRG_413:g.64985T>G
LRG_413p1:p.Ser259Ala
LRG_413p2:p.Ser259Ala
NC_000003.11:g.12645694A>C
NM_001354689.3(RAF1):c.775T>G
NM_002880.3:c.775T>G
NR_148940.3:n.1106T>G
NR_148941.3:n.1106T>G
NR_148942.3:n.1106T>G

Protein change:

S145A

Links:

dbSNP: rs3730271

NCBI 1000 Genomes Browser:

rs3730271

Molecular consequence:

NM_001354689.3:c.775T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354690.3:c.775T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.532T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.532T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.676T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.532T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.433T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.775T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.1106T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.1106T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3:n.1106T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: RASopathy
Synonyms:: rasopathies; Noonan spectrum disorder
Identifiers:: MONDO: MONDO:0021060; MedGen: C5555857

Recent activity

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E3 ubiquitin-protein ligase CHFR isoform 2 [Mus musculus]
E3 ubiquitin-protein ligase CHFR isoform 2 [Mus musculus]
gi|188497681|ref|NP_766305.2|

Protein
epithelial sodium channel, gamma subunit [Rattus norvegicus]
epithelial sodium channel, gamma subunit [Rattus norvegicus]
gi|458850|emb|CAA54905.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001424749	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Pathogenic (Jun 25, 2020)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001424749

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Pathogenic
(Jun 25, 2020)

germline

curation

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	curation

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV001424749.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The c.775T>G (p.Ser259Ala) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported as a confirmed de novo occurrence in 2 probands (PS2_VeryStrong; SCV000808501.1). The variant has been identified in 1 proband with Noonan syndrome (PS4_Supporting; SCV000710868.2). At least 2 other pathogenic missense variants have been previously identified at the Ser259 codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40601, 44633). A functional assay has been performed on c.775T>G (p.Ser259Ala), but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:23391722). Finally, the variant is located in RAF1, 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). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4_Supporting, PM5_Strong, PM2, PP2.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 13, 2023

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