NM_002017.5(FLI1):c.1019G>A (p.Arg340His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 28, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000493355.3

Allele description [Variation Report for NM_002017.5(FLI1):c.1019G>A (p.Arg340His)]

NM_002017.5(FLI1):c.1019G>A (p.Arg340His)

Gene:

FLI1:Fli-1 proto-oncogene, ETS transcription factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q24.3

Genomic location:

Preferred name:

NM_002017.5(FLI1):c.1019G>A (p.Arg340His)

HGVS:

NC_000011.10:g.128810648G>A
NG_032912.1:g.129114G>A
NM_001167681.3:c.920G>A
NM_001271010.2:c.821G>A
NM_001271012.2:c.440G>A
NM_002017.5:c.1019G>AMANE SELECT
NP_001161153.1:p.Arg307His
NP_001257939.1:p.Arg274His
NP_001257941.1:p.Arg147His
NP_002008.2:p.Arg340His
LRG_646t1:c.920G>A
LRG_646t2:c.821G>A
LRG_646t3:c.440G>A
LRG_646t4:c.1019G>A
LRG_646:g.129114G>A
LRG_646p1:p.Arg307His
LRG_646p2:p.Arg274His
LRG_646p3:p.Arg147His
LRG_646p4:p.Arg340His
NC_000011.9:g.128680543G>A
NM_002017.4:c.1019G>A

Protein change:

R147H

Links:

dbSNP: rs1131691896

NCBI 1000 Genomes Browser:

rs1131691896

Molecular consequence:

NM_001167681.3:c.920G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001271010.2:c.821G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001271012.2:c.440G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_002017.5:c.1019G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000583094	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Feb 15, 2016)	germline	clinical testing	Citation Link,
SCV004312777	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 28, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000583094

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely pathogenic
(Feb 15, 2016)

germline

clinical testing

Citation Link,

SCV004312777

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 28, 2023)

germline

clinical testing

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

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
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Details of each submission

From GeneDx, SCV000583094.4

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

Description

The R340H variant in the FLI1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R340H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R340H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position the ETS DNA binding domain of FLI1 that is conserved across species. Missense variants in this domain have been shown to abolish DNA binding and reduce transcription activity by 60% (Stockley et al., 2013). In silico analysis predicts this variant is probably damaging to the protein structure/function. The R340H variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded.

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004312777.1

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 340 of the FLI1 protein (p.Arg340His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 430313). 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 FLI1 protein function. 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.

#	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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