NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 8, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000159086.7

Allele description [Variation Report for NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)]

NM_002880.4(RAF1):c.1472C>T (p.Thr491Ile)

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.1472C>T (p.Thr491Ile)

Other names:

p.T491I:ACA>ATA; NM_002880.3(RAF1):c.1472C>T; NM_002880.4(RAF1):c.1472C>T

HGVS:

NC_000003.12:g.12585745G>A
NG_007467.1:g.83435C>T
NM_001354689.3:c.1532C>T
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_002880.4:c.1472C>TMANE SELECT
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
NM_002880.3:c.1472C>T
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_002880.4: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]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000209029	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Sep 8, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000209029

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Sep 8, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From GeneDx, SCV000209029.14

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Observed in multiple unrelated patients with Noonan spectrum disorders tested at GeneDx, in the published literature, and in ClinVar, including apparently de novo in an affected patient (Pandit et al., 2007; ClinVar SCV000061338.4; ClinVar); about 80% of individuals with a RAF1 variant develop hypertrophic cardiomyopathy; Published functional studies demonstrate impaired MEK kinase expression and constitutive ERK activation (Pandit et al., 2007) and show the variant is located in the activation segment of the CR3 (conserved region 3), a critical functional domain; Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 26214590, 27236105, 23093928, 24803665, 25907612, 25333451, 27753652, 30732632, 31219622, 34328347, 29493581, 17603483, 9689060, 15520807, 17603482, 19020799)

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

Last Updated: Apr 13, 2025

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