NM_001354689.3(RAF1):c.768G>T (p.Arg256Ser) AND Rasopathy

Clinical significance:Pathogenic (Last evaluated: Apr 3, 2017)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000523940.1

Allele description [Variation Report for NM_001354689.3(RAF1):c.768G>T (p.Arg256Ser)]

NM_001354689.3(RAF1):c.768G>T (p.Arg256Ser)

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_001354689.3(RAF1):c.768G>T (p.Arg256Ser)
Other names:
p.R256S:AGG>AGT; NM_002880.3(RAF1):c.768G>T
HGVS:
  • NC_000003.12:g.12604202C>A
  • NG_007467.1:g.64978G>T
  • NM_001354689.3:c.768G>TMANE SELECT
  • NM_001354690.2:c.768G>T
  • NM_001354691.2:c.525G>T
  • NM_001354692.2:c.525G>T
  • NM_001354693.2:c.669G>T
  • NM_001354694.2:c.525G>T
  • NM_001354695.2:c.426G>T
  • NM_002880.3:c.768G>T
  • NP_001341618.1:p.Arg256Ser
  • NP_001341619.1:p.Arg256Ser
  • NP_001341620.1:p.Arg175Ser
  • NP_001341621.1:p.Arg175Ser
  • NP_001341622.1:p.Arg223Ser
  • NP_001341623.1:p.Arg175Ser
  • NP_001341624.1:p.Arg142Ser
  • NP_002871.1:p.Arg256Ser
  • LRG_413t1:c.768G>T
  • LRG_413t2:c.768G>T
  • LRG_413:g.64978G>T
  • LRG_413p1:p.Arg256Ser
  • LRG_413p2:p.Arg256Ser
  • NC_000003.11:g.12645701C>A
  • NR_148940.2:n.1099G>T
  • NR_148941.2:n.1099G>T
  • NR_148942.2:n.1099G>T
  • P04049:p.Arg256Ser
  • c.768G>T
Protein change:
R142S
Links:
UniProtKB: P04049#VAR_037807; dbSNP: rs397516826
NCBI 1000 Genomes Browser:
rs397516826
Molecular consequence:
  • NM_001354689.3:c.768G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.768G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.2:c.525G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.2:c.525G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.669G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.2:c.525G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.2:c.426G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.768G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.1099G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.1099G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.1099G>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000616377ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Pathogenic
(Apr 3, 2017)
germlinecuration

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen RASopathy Variant Curation Expert Panel, SCV000616377.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.768G>T (p.Arg256Ser) variant in RAF1 has been reported in the literature in 1 individual with clinical features of Noonan syndrome and one individual with clinical features of Noonan syndrome with multiple lentigines. 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.Arg256Ser variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Arg256Ser variant may impact protein function (PS3; 20679480). 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). 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): PP2, PP3, PM1, PM2, PS3.

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

Last Updated: Sep 29, 2021

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