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

Clinical significance:Uncertain significance (Last evaluated: Mar 9, 2020)

Review status:3 stars out of maximum of 4 stars

reviewed by expert panel

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000696020.4

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]

Condition(s)

Name:
Rasopathy
Synonyms:
rasopathies; Noonan spectrum disorder
Identifiers:
MONDO: MONDO:0021060; MedGen: CN166718

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000824563Invitaecriteria provided, single submitter
Pathogenic
(Sep 17, 2020)
germlineclinical testing

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

SCV001335315ClinGen RASopathy Variant Curation Expert Panelreviewed by expert panel
Uncertain significance
(Mar 9, 2020)
germlinecuration

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

Citation Link

Summary from all submissions

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000824563.3

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

Description

This sequence change replaces threonine with isoleucine at codon 260 of the RAF1 protein (p.Thr260Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Noonan syndrome (PMID: 17603483, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 222774). Experimental studies have shown that this variant affects RAF1 protein function (PMID: 20679480). This variant disrupts the p.Thr260 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From ClinGen RASopathy Variant Curation Expert Panel, SCV001335315.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (1)

Description

The c.779C>T (p.Thr260Ile) variant in RAF1 was absent from large population databases (PM2; gnomad.broadinstitute.org). It occurs in the CR2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 20679480). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 17603483; Blueprint Genetics internal data, SCV000264163.2; Invitae internal data, SCV000824563.1; Ambry internal data, SCV000740058.2; GeneDx internal data, SCV000582743.4). Although criteria suggest that this variant is likely pathogenic given its location and in vitro functional studies, the lack of clear clinical presentations of a RASopathy phenotype supports that this variant is of uncertain significance at this time. RASopathy-specific ACMG/AMP criteria applied: PS3, PM1, PM2, PP2.

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

Last Updated: Aug 27, 2021

Support Center