NM_001354689.3(RAF1):c.1532C>T (p.Thr511Ile) AND Noonan syndrome

Clinical significance:Pathogenic (Last evaluated: May 28, 2013)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000037676.4

Allele description [Variation Report for NM_001354689.3(RAF1):c.1532C>T (p.Thr511Ile)]

NM_001354689.3(RAF1):c.1532C>T (p.Thr511Ile)

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.1532C>T (p.Thr511Ile)
Other names:
p.T491I:ACA>ATA; NM_002880.3(RAF1):c.1472C>T
HGVS:
  • NC_000003.12:g.12585745G>A
  • NC_000003.12:g.12585745G>A
  • NG_007467.1:g.83435C>T
  • NM_001354689.3:c.1532C>TMANE SELECT
  • NM_001354690.3:c.1472C>T
  • NM_001354691.3:c.1229C>T
  • NM_001354692.3:c.1229C>T
  • NM_001354693.3:c.1373C>T
  • NM_001354694.3:c.1289C>T
  • NM_001354695.3:c.1130C>T
  • NM_002880.3:c.1472C>T
  • NM_002880.4:c.1472C>T
  • NP_001341618.1:p.Thr511Ile
  • NP_001341619.1:p.Thr491Ile
  • NP_001341620.1:p.Thr410Ile
  • NP_001341621.1:p.Thr410Ile
  • NP_001341622.1:p.Thr458Ile
  • NP_001341623.1:p.Thr430Ile
  • NP_001341624.1:p.Thr377Ile
  • NP_002871.1:p.Thr491Ile
  • NP_002871.1:p.Thr491Ile
  • LRG_413t1:c.1472C>T
  • LRG_413t2:c.1532C>T
  • LRG_413:g.83435C>T
  • LRG_413p1:p.Thr491Ile
  • LRG_413p2:p.Thr511Ile
  • NC_000003.11:g.12627244G>A
  • NC_000003.11:g.12627244G>A
  • NR_148940.3:n.1916C>T
  • NR_148941.3:n.1862C>T
  • NR_148942.3:n.1801C>T
  • P04049:p.Thr491Ile
  • c.1472C>T
Protein change:
T377I
Links:
UniProtKB: P04049#VAR_037818; dbSNP: rs80338799
NCBI 1000 Genomes Browser:
rs80338799
Molecular consequence:
  • NM_001354689.3:c.1532C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.3:c.1472C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.3:c.1229C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.3:c.1229C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.3:c.1373C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.3:c.1289C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.3:c.1130C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.1472C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.4:c.1472C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.3:n.1916C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.3:n.1862C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.3:n.1801C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
3

Condition(s)

Name:
Noonan syndrome (NS)
Synonyms:
Noonan's syndrome; Pseudo-Turner syndrome
Identifiers:
MONDO: MONDO:0018997; MeSH: D009634; MedGen: C0028326; OMIM: PS163950

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000061338Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(May 28, 2013)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000510557Database of Curated Mutations (DoCM)no assertion criteria providedLikely pathogenic
(May 13, 2016)
somaticliterature only

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot provided43not providednot providednot providedclinical testing
not providedsomaticyesnot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

Pandit B, Sarkozy A, Pennacchio LA, Carta C, Oishi K, Martinelli S, Pogna EA, Schackwitz W, Ustaszewska A, Landstrom A, Bos JM, Ommen SR, Esposito G, Lepri F, Faul C, Mundel P, López Siguero JP, Tenconi R, Selicorni A, Rossi C, Mazzanti L, Torrente I, et al.

Nat Genet. 2007 Aug;39(8):1007-12. Epub 2007 Jul 1.

PubMed [citation]
PMID:
17603483

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000061338.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided4not providednot providedclinical testing PubMed (2)

Description

The Thr491Ile has been identified in our laboratory in two probands with clinica l features of Noonan syndrome. In addition, this variant was not identified in t he parents of one proband in our laboratory, and therefore occurred de novo. Thi s variant has also been reported in the literature in one individual with clinic al features of Noonan syndrome and was not identified in 210 control individuals (Pandit 2007). Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, and SIFT) suggest that the Thr491Ile variant may impact the protein. In summary, this variant meets our criteria to be classified as pathoge nic based on its de novo occurrence (http://pcpgm.partners.org/LMM).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided4not provided3not provided

From Database of Curated Mutations (DoCM), SCV000510557.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1somaticyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 24, 2021

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