NM_002880.4(RAF1):c.779C>T (p.Thr260Ile) AND RASopathy

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 9, 2020
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000696020.10

Allele description [Variation Report for NM_002880.4(RAF1):c.779C>T (p.Thr260Ile)]

NM_002880.4(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_002880.4(RAF1):c.779C>T (p.Thr260Ile)

HGVS:

NC_000003.12:g.12604191G>A
NG_007467.1:g.64989C>T
NM_001354689.3:c.779C>T
NM_001354690.3:c.779C>T
NM_001354691.3:c.536C>T
NM_001354692.3:c.536C>T
NM_001354693.3:c.680C>T
NM_001354694.3:c.536C>T
NM_001354695.3:c.437C>T
NM_002880.4:c.779C>TMANE SELECT
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
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
NM_002880.3:c.779C>T
NR_148940.3:n.1110C>T
NR_148941.3:n.1110C>T
NR_148942.3: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_001354690.3:c.779C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354691.3:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354692.3:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354693.3:c.680C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354694.3:c.536C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354695.3:c.437C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002880.4:c.779C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_148940.3:n.1110C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148941.3:n.1110C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_148942.3: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: C5555857

Recent activity

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ralf-like 9 [Arabidopsis thaliana]
ralf-like 9 [Arabidopsis thaliana]
gi|18407238|ref|NP_564779.1|

Protein
breast cancer type 1 susceptibility protein isoform 124 [Homo sapiens]
breast cancer type 1 susceptibility protein isoform 124 [Homo sapiens]
gi|2255444212|ref|NP_001395403.1|

Protein
LOC129599678 [Paramacrobiotus metropolitanus]
LOC129599678 [Paramacrobiotus metropolitanus]
Gene ID:129599678

Gene

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000824563	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20679480, 17603483, 28492532
SCV001335315	ClinGen RASopathy Variant Curation Expert Panel	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Uncertain significance (Mar 9, 2020)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000824563

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2022)

germline

clinical testing

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

SCV001335315

ClinGen RASopathy Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RASopathy ACMG Specifications v1)

Uncertain significance
(Mar 9, 2020)

germline

curation

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000824563.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Experimental studies have shown that this missense change affects RAF1 function (PMID: 20679480). For these reasons, this variant has been classified as Pathogenic. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RAF1 protein function. ClinVar contains an entry for this variant (Variation ID: 222774). This missense change 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. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 260 of the RAF1 protein (p.Thr260Ile).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen RASopathy Variant Curation Expert Panel, SCV001335315.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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