NM_001354689.3(RAF1):c.779C>T (p.Thr260Ile) AND Cardiovascular phenotype

Clinical significance:Likely pathogenic (Last evaluated: Oct 31, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000617372.1

Allele description [Variation Report for NM_001354689.3(RAF1):c.779C>T (p.Thr260Ile)]

NM_001354689.3(RAF1):c.779C>T (p.Thr260Ile)

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.779C>T (p.Thr260Ile)
HGVS:
  • NC_000003.12:g.12604191G>A
  • NG_007467.1:g.64989C>T
  • NM_001354689.3:c.779C>TMANE SELECT
  • NM_001354690.2:c.779C>T
  • NM_001354691.2:c.536C>T
  • NM_001354692.2:c.536C>T
  • NM_001354693.2:c.680C>T
  • NM_001354694.2:c.536C>T
  • NM_001354695.2:c.437C>T
  • NM_002880.3:c.779C>T
  • NP_001341618.1:p.Thr260Ile
  • NP_001341619.1:p.Thr260Ile
  • NP_001341620.1:p.Thr179Ile
  • NP_001341621.1:p.Thr179Ile
  • NP_001341622.1:p.Thr227Ile
  • NP_001341623.1:p.Thr179Ile
  • NP_001341624.1:p.Thr146Ile
  • NP_002871.1:p.Thr260Ile
  • LRG_413t1:c.779C>T
  • LRG_413t2:c.779C>T
  • LRG_413:g.64989C>T
  • LRG_413p1:p.Thr260Ile
  • LRG_413p2:p.Thr260Ile
  • NC_000003.11:g.12645690G>A
  • NM_002880.3(RAF1):c.779C>T
  • NR_148940.2:n.1110C>T
  • NR_148941.2:n.1110C>T
  • NR_148942.2:n.1110C>T
  • P04049:p.Thr260Ile
Protein change:
T146I
Links:
UniProtKB: P04049#VAR_037810; dbSNP: rs869025501
NCBI 1000 Genomes Browser:
rs869025501
Molecular consequence:
  • NM_001354689.3:c.779C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.779C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354691.2:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354692.2:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354694.2:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354695.2:c.437C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.779C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.1110C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.1110C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.1110C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Cardiovascular phenotype
Identifiers:
MedGen: CN230736

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000740058Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Oct 31, 2016)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

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

Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling.

Molzan M, Schumacher B, Ottmann C, Baljuls A, Polzien L, Weyand M, Thiel P, Rose R, Rose M, Kuhenne P, Kaiser M, Rapp UR, Kuhlmann J, Ottmann C.

Mol Cell Biol. 2010 Oct;30(19):4698-711. doi: 10.1128/MCB.01636-09. Epub 2010 Aug 2.

PubMed [citation]
PMID:
20679480
PMCID:
PMC2950525
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000740058.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)

Description

The p.T260I variant (also known as c.779C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 779. The threonine at codon 260 is replaced by isoleucine, an amino acid with similar properties. This alteration is located in the consensus recognition site for 14-3-3, which is a hotspot for Noonan syndrome (NS) mutations. Mutations in this region have been associated with a high prevalence of hypertrophic cardiomyopathy (HCM), and this variant has been previously reported in an HCM cohort (Pandit B et al. Nat. Genet. 2007;39:1007-12). Functional studies have demonstrated that this alteration leads to decreased phosphorylation of an invariant phosphorylated serine in the 14-3-3 recognition site, impaired 14-3-3 binding affinity, and increased RAF1 catalytic activity (Molzan M et al. Mol. Cell. Biol. 2010;30:4698-711). Furthermore, a likely pathogenic alteration affecting the same codon (p.T260R) has been reported in an individual with NS (Pandit B et al. Nat. Genet. 2007;39:1007-12). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Aug 27, 2021

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