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NM_002880.4(RAF1):c.788T>G (p.Val263Gly) AND RASopathy

Germline classification:
Likely pathogenic (3 submissions)
Last evaluated:
Apr 3, 2017
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:
RCV000523845.12

Allele description [Variation Report for NM_002880.4(RAF1):c.788T>G (p.Val263Gly)]

NM_002880.4(RAF1):c.788T>G (p.Val263Gly)

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.788T>G (p.Val263Gly)
Other names:
p.V263G:GTC>GGC; NM_002880.3(RAF1):c.788T>G
HGVS:
  • NC_000003.12:g.12604182A>C
  • NG_007467.1:g.64998T>G
  • NM_001354689.3:c.788T>G
  • NM_001354690.3:c.788T>G
  • NM_001354691.3:c.545T>G
  • NM_001354692.3:c.545T>G
  • NM_001354693.3:c.689T>G
  • NM_001354694.3:c.545T>G
  • NM_001354695.3:c.446T>G
  • NM_002880.4:c.788T>GMANE SELECT
  • NP_001341618.1:p.Val263Gly
  • NP_001341619.1:p.Val263Gly
  • NP_001341620.1:p.Val182Gly
  • NP_001341621.1:p.Val182Gly
  • NP_001341622.1:p.Val230Gly
  • NP_001341623.1:p.Val182Gly
  • NP_001341624.1:p.Val149Gly
  • NP_002871.1:p.Val263Gly
  • NP_002871.1:p.Val263Gly
  • LRG_413t1:c.788T>G
  • LRG_413t2:c.788T>G
  • LRG_413:g.64998T>G
  • LRG_413p1:p.Val263Gly
  • LRG_413p2:p.Val263Gly
  • NC_000003.11:g.12645681A>C
  • NM_002880.3:c.788T>G
  • NR_148940.3:n.1119T>G
  • NR_148941.3:n.1119T>G
  • NR_148942.3:n.1119T>G
  • c.788T>G
Protein change:
V149G
Links:
dbSNP: rs397516830
NCBI 1000 Genomes Browser:
rs397516830
Molecular consequence:
  • NM_001354689.3:c.788T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.788T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.545T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.545T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.689T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.545T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.446T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.788T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1119T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1119T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1119T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000616423ClinGen RASopathy Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)		Likely pathogenic
(Apr 3, 2017) 		germlinecuration

PubMed (1)
[See all records that cite this PMID]

Citation Link,

SCV000920144Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Apr 1, 2020) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001234889Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Oct 22, 2023) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

ClinGen's RASopathy Expert Panel consensus methods for variant interpretation.

Gelb BD, Cavé H, Dillon MW, Gripp KW, Lee JA, Mason-Suares H, Rauen KA, Williams B, Zenker M, Vincent LM; ClinGen RASopathy Working Group..

Genet Med. 2018 Nov;20(11):1334-1345. doi: 10.1038/gim.2018.3. Epub 2018 Mar 1.

PubMed [citation]
PMID:
29493581
PMCID:
PMC6119537

Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina.

Chinton J, Huckstadt V, Moresco A, Gravina LP, Obregon MG.

Arch Argent Pediatr. 2019 Oct 1;117(5):330-337. doi: 10.5546/aap.2019.eng.330. English, Spanish.

PubMed [citation]
PMID:
31560489
See all PubMed Citations (8)

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616423.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.788T>G (p.Val263Gly) variant in RAF1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR ID: 26957; ClinVar SCV000061370.9). The p.Val263Gly variant has been identified in 6 other independent occurrences in patients with a RASopathy (PS4 not met; Partners LMM, Blueprint genetics, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 500188, 506381, 28338; ClinVar SCV000209021.9, SCV000207170.1). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 496189, 40608). 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). 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.Val263Gly 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, PM5, PM2, PM1, PP3, PP2.

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000920144.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

RAF1 c.788T>G (p.Val263Gly) results in a non-conservative amino acid change located in a region of the CR2 functional domain of the encoded protein sequence supporting pathogenicity, as defined by the ClinGen RASopathy Expert Panel (PM1; PMID 29493581). Five of five in-silico tools predict a damaging effect of the variant on protein function (PP3). The variant was absent in 251466 control chromosomes in the gnomAD database (PM2). c.788T>G has been reported in the literature in at least 5 individuals affected with Noonan Syndrome and Related Conditions (e.g. Chen_2019, Clinton_2019, Ghedira_2018, Rodriguez_2019, Schulz_2012) (PS4). The variant was reported as a de novo occurrence (confirmed via parental testing) in at least 3 of the documented patients (e.g. Chen_2019, Ghedira_2018, Schulz_2012) (PS2). Additional patients with clinical features of a RASopathy or specifically Noonan syndrome have been reported in the ClinVar database (SCV000616423.3, SCV000061370.6). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, a different variant affecting the same amino acid, p.Val263Ala, has been functionally assessed and showed increased in vitro kinase and ERK activation, behaving as a gain-of-function mutant (PMID 17603482). Kobayashi et al (2010) (PMID 20052757) report in their study that mutations in RAF1 were clustered in the conserved region 2 (CR2) domain, which carries an inhibitory phosphorylation site (S259). Functional studies suggest that dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain. The ClinGen RASopathy Variant Curation Expert Panel cites the variant in ClinVar (evaluation after 2014) as likely pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic.

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234889.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 263 of the RAF1 protein (p.Val263Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 30157809, 30732632). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 40607). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. This variant disrupts the p.Val263 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603482; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024