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NM_002880.4(RAF1):c.785A>T (p.Asn262Ile) AND RASopathy

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Nov 12, 2024
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001232030.9

Allele description [Variation Report for NM_002880.4(RAF1):c.785A>T (p.Asn262Ile)]

NM_002880.4(RAF1):c.785A>T (p.Asn262Ile)

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.785A>T (p.Asn262Ile)
Other names:
p.N262I:AAT>ATT
HGVS:
  • NC_000003.12:g.12604185T>A
  • NG_007467.1:g.64995A>T
  • NM_001354689.3:c.785A>T
  • NM_001354690.3:c.785A>T
  • NM_001354691.3:c.542A>T
  • NM_001354692.3:c.542A>T
  • NM_001354693.3:c.686A>T
  • NM_001354694.3:c.542A>T
  • NM_001354695.3:c.443A>T
  • NM_002880.4:c.785A>TMANE SELECT
  • NP_001341618.1:p.Asn262Ile
  • NP_001341619.1:p.Asn262Ile
  • NP_001341620.1:p.Asn181Ile
  • NP_001341621.1:p.Asn181Ile
  • NP_001341622.1:p.Asn229Ile
  • NP_001341623.1:p.Asn181Ile
  • NP_001341624.1:p.Asn148Ile
  • NP_002871.1:p.Asn262Ile
  • NP_002871.1:p.Asn262Ile
  • LRG_413t1:c.785A>T
  • LRG_413t2:c.785A>T
  • LRG_413:g.64995A>T
  • LRG_413p1:p.Asn262Ile
  • LRG_413p2:p.Asn262Ile
  • NC_000003.11:g.12645684T>A
  • NM_002880.3:c.785A>T
  • NR_148940.3:n.1116A>T
  • NR_148941.3:n.1116A>T
  • NR_148942.3:n.1116A>T
Protein change:
N148I
Links:
dbSNP: rs730881010
NCBI 1000 Genomes Browser:
rs730881010
Molecular consequence:
  • NM_001354689.3:c.785A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.785A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.542A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.542A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.686A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.542A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.443A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.785A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1116A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1116A>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1116A>T - 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
SCV001404573Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Nov 12, 2024) 		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

Citations

PubMed

Diagnosis of Noonan syndrome and related disorders using target next generation sequencing.

Lepri FR, Scavelli R, Digilio MC, Gnazzo M, Grotta S, Dentici ML, Pisaneschi E, Sirleto P, Capolino R, Baban A, Russo S, Franchin T, Angioni A, Dallapiccola B.

BMC Med Genet. 2014 Jan 23;15:14. doi: 10.1186/1471-2350-15-14.

PubMed [citation]
PMID:
24451042
PMCID:
PMC3915031

Molecular and clinical analysis of RAF1 in Noonan syndrome and related disorders: dephosphorylation of serine 259 as the essential mechanism for mutant activation.

Kobayashi T, Aoki Y, Niihori T, Cavé H, Verloes A, Okamoto N, Kawame H, Fujiwara I, Takada F, Ohata T, Sakazume S, Ando T, Nakagawa N, Lapunzina P, Meneses AG, Gillessen-Kaesbach G, Wieczorek D, Kurosawa K, Mizuno S, Ohashi H, David A, Philip N, et al.

Hum Mutat. 2010 Mar;31(3):284-94. doi: 10.1002/humu.21187.

PubMed [citation]
PMID:
20052757
See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001404573.6

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

Description

This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 262 of the RAF1 protein (p.Asn262Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RAF1-related conditions (PMID: 24451042). ClinVar contains an entry for this variant (Variation ID: 181517). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt RAF1 function with a positive predictive value of 95%. This variant disrupts the p.Asn262 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20052757, 30732632). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Feb 25, 2025