NM_001354689.3(RAF1):c.781C>A (p.Pro261Thr) AND Rasopathy

Clinical significance:Pathogenic (Last evaluated: Nov 29, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000149827.5

Allele description [Variation Report for NM_001354689.3(RAF1):c.781C>A (p.Pro261Thr)]

NM_001354689.3(RAF1):c.781C>A (p.Pro261Thr)

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.781C>A (p.Pro261Thr)
HGVS:
  • NC_000003.12:g.12604189G>T
  • NG_007467.1:g.64991C>A
  • NM_001354689.3:c.781C>AMANE SELECT
  • NM_001354690.2:c.781C>A
  • NM_001354691.2:c.538C>A
  • NM_001354692.2:c.538C>A
  • NM_001354693.2:c.682C>A
  • NM_001354694.2:c.538C>A
  • NM_001354695.2:c.439C>A
  • NM_002880.3:c.781C>A
  • NP_001341618.1:p.Pro261Thr
  • NP_001341619.1:p.Pro261Thr
  • NP_001341620.1:p.Pro180Thr
  • NP_001341621.1:p.Pro180Thr
  • NP_001341622.1:p.Pro228Thr
  • NP_001341623.1:p.Pro180Thr
  • NP_001341624.1:p.Pro147Thr
  • NP_002871.1:p.Pro261Thr
  • LRG_413t1:c.781C>A
  • LRG_413t2:c.781C>A
  • LRG_413:g.64991C>A
  • LRG_413p1:p.Pro261Thr
  • LRG_413p2:p.Pro261Thr
  • NC_000003.11:g.12645688G>T
  • NM_002880.2:c.781C>A
  • NR_148940.2:n.1112C>A
  • NR_148941.2:n.1112C>A
  • NR_148942.2:n.1112C>A
  • c.781C>A
Protein change:
P147T
Links:
dbSNP: rs121434594
NCBI 1000 Genomes Browser:
rs121434594
Molecular consequence:
  • NM_001354689.3:c.781C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.781C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.2:c.538C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.2:c.538C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.682C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.2:c.538C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.2:c.439C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.781C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.1112C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.1112C>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.1112C>A - 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
SCV000196669Baylor Geneticsno assertion criteria providedPathogenicunknownclinical testing

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

SCV000776868Invitaecriteria provided, single submitter
Pathogenic
(Nov 29, 2019)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Alterations in RAS-MAPK genes in 200 Spanish patients with Noonan and other neuro-cardio-facio-cutaneous syndromes. Genotype and cardiopathy.

Ezquieta B, Santomé JL, Carcavilla A, Guillén-Navarro E, Pérez-Aytés A, Sánchez del Pozo J, García-Miñaur S, Castillo E, Alonso M, Vendrell T, Santana A, Maroto E, Galbis L.

Rev Esp Cardiol (Engl Ed). 2012 May;65(5):447-55. doi: 10.1016/j.recesp.2011.12.016. Epub 2012 Mar 31. English, Spanish.

PubMed [citation]
PMID:
22465605

Spectrum of mutations in Noonan syndrome and their correlation with phenotypes.

Lee BH, Kim JM, Jin HY, Kim GH, Choi JH, Yoo HW.

J Pediatr. 2011 Dec;159(6):1029-35. doi: 10.1016/j.jpeds.2011.05.024. Epub 2011 Jul 23.

PubMed [citation]
PMID:
21784453
See all PubMed Citations (7)

Details of each submission

From Baylor Genetics, SCV000196669.1

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

Description

Variant classified using ACMG guidelines

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

From Invitae, SCV000776868.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change replaces proline with threonine at codon 261 of the RAF1 protein (p.Pro261Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in individuals affected with Noonan syndrome (PMID:22465605, 21784453, 29084544). ClinVar contains an entry for this variant (Variation ID: 40604). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Pro261Ser) has been determined to be pathogenic in several individuals affected with Noonan syndrome (PMID: 17603482, 20683980, 17603483). This suggests that the proline residue is critical for RAF1 protein function and that other missense substitutions at this position may also be pathogenic. 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: Jul 7, 2021

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