NM_006267.5(RANBP2):c.1966A>G (p.Ile656Val) AND Familial acute necrotizing encephalopathy

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Mar 15, 2024
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:: RCV000008870.12

Allele description [Variation Report for NM_006267.5(RANBP2):c.1966A>G (p.Ile656Val)]

NM_006267.5(RANBP2):c.1966A>G (p.Ile656Val)

Gene:

RANBP2:RAN binding protein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q13

Genomic location:

Preferred name:

NM_006267.5(RANBP2):c.1966A>G (p.Ile656Val)

HGVS:

NC_000002.12:g.108753474A>G
NG_012210.1:g.38994A>G
NM_006267.5:c.1966A>GMANE SELECT
NP_006258.3:p.Ile656Val
NC_000002.11:g.109369930A>G
NM_006267.4:c.1966A>G
P49792:p.Ile656Val

Protein change:

I656V; ILE656VAL

Links:

UniProtKB: P49792#VAR_054999; OMIM: 601181.0003; dbSNP: rs121434504

NCBI 1000 Genomes Browser:

rs121434504

Molecular consequence:

NM_006267.5:c.1966A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial acute necrotizing encephalopathy
Synonyms:: Encephalopathy, acute, infection-induced, 3, suceptibility to; Susceptibility to Acute Necrotizing Encephalopathy 1
Identifiers:: MONDO: MONDO:0011953; MedGen: C2675556; Orphanet: 88619; OMIM: 608033

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lipopolysaccharide assembly protein LapB [Brachyspira pilosicoli]
lipopolysaccharide assembly protein LapB [Brachyspira pilosicoli]
gi|503009020|ref|WP_013243996.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000029080	OMIM	no assertion criteria provided	risk factor (Jan 1, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000212037	GeneReviews	no classification provided	not provided	germline	literature only
SCV001135923	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002296791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 30, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19118815, 22030434, 28492532
SCV005049751	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 15, 2024)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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	literature only
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Infection-triggered familial or recurrent cases of acute necrotizing encephalopathy caused by mutations in a component of the nuclear pore, RANBP2.

Neilson DE, Adams MD, Orr CM, Schelling DK, Eiben RM, Kerr DS, Anderson J, Bassuk AG, Bye AM, Childs AM, Clarke A, Crow YJ, Di Rocco M, Dohna-Schwake C, Dueckers G, Fasano AE, Gika AD, Gionnis D, Gorman MP, Grattan-Smith PJ, Hackenberg A, Kuster A, et al.

Am J Hum Genet. 2009 Jan;84(1):44-51. doi: 10.1016/j.ajhg.2008.12.009.

PubMed [citation]

PMID:: 19118815
PMCID:: PMC2668029

Recurrent acute necrotizing encephalopathy in a canadian aboriginal child.

Howayyer E, Mhanni AA, Wrogemann J, Salman MS.

Can J Neurol Sci. 2011 Nov;38(6):925-8. No abstract available.

PubMed [citation]

PMID:: 22030434

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000029080.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

In affected members of a family with acute necrotizing encephalopathy (608033), Neilson et al. (2009) identified a heterozygous c.2094A-G transition in the RANBP2 gene, resulting in an ile656-to-val (I656V) substitution in a highly conserved residue in the LRD. The mutation was not found in 200 controls.

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

From GeneReviews, SCV000212037.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

#	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 Mendelics, SCV001135923.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002296791.3

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

Description

This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 656 of the RANBP2 protein (p.Ile656Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with acute necrotizing encephalopathy (PMID: 19118815, 22030434). This variant is also known as c.2094A>G, g.33868A>G. ClinVar contains an entry for this variant (Variation ID: 8365). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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

From Baylor Genetics, SCV005049751.1

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

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

Last Updated: Sep 29, 2024

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