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NM_002880.4(RAF1):c.786T>G (p.Asn262Lys) AND RASopathy

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Apr 26, 2023
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:
RCV003654584.1

Allele description [Variation Report for NM_002880.4(RAF1):c.786T>G (p.Asn262Lys)]

NM_002880.4(RAF1):c.786T>G (p.Asn262Lys)

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.786T>G (p.Asn262Lys)
HGVS:
  • NC_000003.12:g.12604184A>C
  • NG_007467.1:g.64996T>G
  • NM_001354689.3:c.786T>G
  • NM_001354690.3:c.786T>G
  • NM_001354691.3:c.543T>G
  • NM_001354692.3:c.543T>G
  • NM_001354693.3:c.687T>G
  • NM_001354694.3:c.543T>G
  • NM_001354695.3:c.444T>G
  • NM_002880.4:c.786T>GMANE SELECT
  • NP_001341618.1:p.Asn262Lys
  • NP_001341619.1:p.Asn262Lys
  • NP_001341620.1:p.Asn181Lys
  • NP_001341621.1:p.Asn181Lys
  • NP_001341622.1:p.Asn229Lys
  • NP_001341623.1:p.Asn181Lys
  • NP_001341624.1:p.Asn148Lys
  • NP_002871.1:p.Asn262Lys
  • NP_002871.1:p.Asn262Lys
  • LRG_413t1:c.786T>G
  • LRG_413t2:c.786T>G
  • LRG_413:g.64996T>G
  • LRG_413p1:p.Asn262Lys
  • LRG_413p2:p.Asn262Lys
  • NC_000003.11:g.12645683A>C
  • NM_002880.3:c.786T>G
  • NR_148940.3:n.1117T>G
  • NR_148941.3:n.1117T>G
  • NR_148942.3:n.1117T>G
Protein change:
N148K
Molecular consequence:
  • NM_001354689.3:c.786T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.786T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.543T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.543T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.687T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.543T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.444T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.786T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1117T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1117T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1117T>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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004509167Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Apr 26, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Clinical and mutation profile of pediatric patients with RASopathy-associated hypertrophic cardiomyopathy: results from a Chinese cohort.

Chen H, Li X, Liu X, Wang J, Zhang Z, Wu J, Huang M, Guo Y, Li F, Wang X, Fu L.

Orphanet J Rare Dis. 2019 Feb 7;14(1):29. doi: 10.1186/s13023-019-1010-z.

PubMed [citation]
PMID:
30732632
PMCID:
PMC6367752

Fetal exome sequencing for isolated increased nuchal translucency: should we be doing it?

Mellis R, Eberhardt RY, Hamilton SJ; PAGE Consortium., McMullan DJ, Kilby MD, Maher ER, Hurles ME, Giordano JL, Aggarwal V, Goldstein DB, Wapner RJ, Chitty LS.

BJOG. 2022 Jan;129(1):52-61. doi: 10.1111/1471-0528.16869. Epub 2021 Sep 14.

PubMed [citation]
PMID:
34411415
PMCID:
PMC9292445
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004509167.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 262 of the RAF1 protein (p.Asn262Lys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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 missense change has been observed in individual(s) with Noonan syndrome and/or prenatal features of this condition (PMID: 30732632, 34411415). In at least one individual the variant was observed to be de novo.

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

Last Updated: Feb 28, 2024