NM_001354689.3(RAF1):c.94A>G (p.Ile32Val) AND Rasopathy

Clinical significance:Uncertain significance (Last evaluated: Oct 28, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000229182.7

Allele description [Variation Report for NM_001354689.3(RAF1):c.94A>G (p.Ile32Val)]

NM_001354689.3(RAF1):c.94A>G (p.Ile32Val)

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.94A>G (p.Ile32Val)
Other names:
p.I32V:ATA>GTA; NM_002880.3(RAF1):c.94A>G
HGVS:
  • NC_000003.12:g.12618628T>C
  • NG_007467.1:g.50552A>G
  • NM_001354689.3:c.94A>GMANE SELECT
  • NM_001354690.2:c.94A>G
  • NM_001354691.2:c.-37A>G
  • NM_001354692.2:c.-37A>G
  • NM_001354693.2:c.94A>G
  • NM_001354694.2:c.-37A>G
  • NM_001354695.2:c.-37A>G
  • NM_002880.3:c.94A>G
  • NP_001341618.1:p.Ile32Val
  • NP_001341619.1:p.Ile32Val
  • NP_001341622.1:p.Ile32Val
  • NP_002871.1:p.Ile32Val
  • LRG_413t1:c.94A>G
  • LRG_413t2:c.94A>G
  • LRG_413:g.50552A>G
  • LRG_413p1:p.Ile32Val
  • LRG_413p2:p.Ile32Val
  • NC_000003.11:g.12660127T>C
  • NR_148940.2:n.425A>G
  • NR_148941.2:n.425A>G
  • NR_148942.2:n.425A>G
Protein change:
I32V
Links:
dbSNP: rs372738063
NCBI 1000 Genomes Browser:
rs372738063
Molecular consequence:
  • NM_001354691.2:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354692.2:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354694.2:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354695.2:c.-37A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354689.3:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354690.2:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354693.2:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002880.3:c.94A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NR_148940.2:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148941.2:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_148942.2:n.425A>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000287747Invitaecriteria provided, single submitter
Uncertain significance
(Oct 28, 2020)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.

Kobayashi Y, Yang S, Nykamp K, Garcia J, Lincoln SE, Topper SE.

Genome Med. 2017 Feb 6;9(1):13. doi: 10.1186/s13073-017-0403-7.

PubMed [citation]
PMID:
28166811
PMCID:
PMC5295186

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]
PMID:
26580448
PMCID:
PMC4734119
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000287747.7

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

Description

This sequence change replaces isoleucine with valine at codon 32 of the RAF1 protein (p.Ile32Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs372738063, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Sep 6, 2021

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