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

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Interpretation:
Uncertain significance​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
5 (Most recent: Jan 7, 2021)
Last evaluated:
Mar 9, 2020
Accession:
VCV000222774.7
Variation ID:
222774
Description:
single nucleotide variant
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NM_001354689.3(RAF1):c.779C>T (p.Thr260Ile)

Allele ID
224260
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p25.2
Genomic location
3: 12604191 (GRCh38) GRCh38 UCSC
3: 12645690 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000003.11:g.12645690G>A
NC_000003.12:g.12604191G>A
NM_001354689.3:c.779C>T MANE Select NP_001341618.1:p.Thr260Ile missense
... more HGVS
Protein change
T260I, T146I, T179I, T227I
Other names
-
Canonical SPDI
NC_000003.12:12604190:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA351736
UniProtKB: P04049#VAR_037810
dbSNP: rs869025501
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 reviewed by expert panel Mar 9, 2020 RCV000696020.4
Likely pathogenic 1 criteria provided, single submitter Feb 3, 2015 RCV000208050.1
Likely pathogenic 1 criteria provided, single submitter May 5, 2017 RCV000494156.1
Likely pathogenic 1 criteria provided, single submitter Oct 31, 2016 RCV000617372.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
RAF1 No evidence available No evidence available GRCh38
GRCh37
556 609

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Mar 09, 2020)
reviewed by expert panel
Method: curation
Rasopathy
(Autosomal dominant inheritance)
Allele origin: germline
ClinGen RASopathy Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001335315.1
Submitted: (Apr 09, 2020)
Evidence details
Publications
PubMed (1)
Other databases
https://erepo.clinicalgenome.org…
Comment:
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 … (more)
Likely pathogenic
(Feb 03, 2015)
criteria provided, single submitter
Method: clinical testing
Primary familial hypertrophic cardiomyopathy
Allele origin: germline
Blueprint Genetics
Accession: SCV000264163.2
Submitted: (Jan 15, 2016)
Evidence details
Publications
PubMed (1)
Likely pathogenic
(May 05, 2017)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000582743.4
Submitted: (Jan 29, 2019)
Evidence details
Comment:
The T260I variant has been published in a patient diagnosed with hypertrophic cardiomyopathy (HCM) (Pandit et al., 2007) with limited evidence. The T260I variant is … (more)
Likely pathogenic
(Oct 31, 2016)
criteria provided, single submitter
Method: clinical testing
Cardiovascular phenotype
Allele origin: germline
Ambry Genetics
Accession: SCV000740058.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
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 … (more)
Pathogenic
(Sep 17, 2020)
criteria provided, single submitter
Method: clinical testing
Rasopathy
Allele origin: germline
Invitae
Accession: SCV000824563.3
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
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 … (more)

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations. Kiel C Molecular systems biology 2014 PMID: 24803665
Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling. Molzan M Molecular and cellular biology 2010 PMID: 20679480
Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Pandit B Nature genetics 2007 PMID: 17603483
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d61ef783-d3ed-4577-9f3c-3f2b6c65e7be - - - -

Text-mined citations for rs869025501...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Aug 27, 2021