NM_006267.5(RANBP2):c.1754C>T (p.Thr585Met) AND Encephalopathy, acute, infection-induced, 3, suceptibility to

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(2);Uncertain significance(1) (Last evaluated: Sep 14, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
6 submissions [Details]
Record status:
current
Accession:
RCV000008868.10

Allele description [Variation Report for NM_006267.5(RANBP2):c.1754C>T (p.Thr585Met)]

NM_006267.5(RANBP2):c.1754C>T (p.Thr585Met)

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.1754C>T (p.Thr585Met)
HGVS:
  • NC_000002.12:g.108751993C>T
  • NG_012210.1:g.37513C>T
  • NM_006267.5:c.1754C>TMANE SELECT
  • NP_006258.3:p.Thr585Met
  • NC_000002.11:g.109368449C>T
  • NM_006267.4:c.1754C>T
  • P49792:p.Thr585Met
Protein change:
T585M; THR585MET
Links:
UniProtKB: P49792#VAR_054997; OMIM: 601181.0001; dbSNP: rs121434502
NCBI 1000 Genomes Browser:
rs121434502
Molecular consequence:
  • NM_006267.5:c.1754C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Encephalopathy, acute, infection-induced, 3, suceptibility to (IIAE3)
Synonyms:
ENCEPHALOPATHY, ACUTE NECROTIZING, SUSCEPTIBILITY TO; Susceptibility to Acute Necrotizing Encephalopathy 1
Identifiers:
MONDO: MONDO:0011953; MedGen: C2675556; Orphanet: 88619; OMIM: 608033

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000029078OMIMno assertion criteria providedrisk factor
(Jan 4, 2011)
germlineliterature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000212035GeneReviewsno assertion criteria providedPathogenic
(Dec 4, 2014)
germlineliterature only

Citation Link,

SCV000734136Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensusno assertion criteria providedPathogenicgermlineclinical testing

SCV000767770Invitaecriteria provided, single submitter
Pathogenic
(Sep 14, 2020)
germlineclinical testing

PubMed (12)
[See all records that cite these PMIDs]

SCV000893546Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Pathogenic
(Oct 31, 2018)
unknownclinical testing

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

SCV001251691Genomic Research Center,Shahid Beheshti University of Medical Sciencescriteria provided, single submitter
Uncertain significance
(May 3, 2020)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing, literature only

Citations

PubMed

Variable clinical course in acute necrotizing encephalopathy and identification of a novel RANBP2 mutation.

Sell K, Storch K, Hahn G, Lee-Kirsch MA, Ramantani G, Jackson S, Neilson D, von der Hagen M, Hehr U, Smitka M.

Brain Dev. 2016 Sep;38(8):777-80. doi: 10.1016/j.braindev.2016.02.007. Epub 2016 Feb 26.

PubMed [citation]
PMID:
26923722

RANBP2 mutation in an Indian child with recurrent acute necrotizing encephalopathy.

Sondhi V, Chakrabarty B, Kumar A, Kohli S, Saxena R, Verma IC, Gulati S.

Brain Dev. 2016 Nov;38(10):937-942. doi: 10.1016/j.braindev.2016.05.007. Epub 2016 Aug 30.

PubMed [citation]
PMID:
27591117
See all PubMed Citations (13)

Details of each submission

From OMIM, SCV000029078.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (2)

Description

In affected members of a family with acute necrotizing encephalopathy (IIAE3; 608033), Neilson et al. (2009) identified a heterozygous 1880C-T transition in the RANBP2 gene, resulting in a thr585-to-met (T585M) substitution in the leucine-rich domain (LRD). The same heterozygous mutation was found in 9 of 15 additional families segregrating with disease. Haplotype analysis did not indicate a founder effect. The mutation was not found in 384 controls, 1,000 individuals from the CEPH genome diversity panel, or in 1,297 multiple sclerosis (126200) patients.

Lonnqvist et al. (2011) identified a heterozygous T585M mutation in 6 affected members of a 3-generation Finnish family with ANE1. Five patients had onset of episodes between age 7 months and 6 years; 1 had a single episode at age 12 years as a sequel of mumps. Two patients had recurrence in childhood. One patient had complete recovery, and 3 patients had recovery with only minor motor impairment, 1 of whom also developed seizures responsive to medication. A fifth patient, who had 2 episodes, was severely mentally retarded with intractable epilepsy at age 35, and a sixth patient had learning disabilities and severe visual impairment. All episodes were preceded by common viral infections. Brain MRI showed that the external capsule and mamillary bodies were affected in all, and the brainstem and thalami in 3.

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

From GeneReviews, SCV000212035.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature onlynot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV000734136.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000767770.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (12)

Description

This sequence change replaces threonine with methionine at codon 585 of the RANBP2 protein (p.Thr585Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been identified in many individuals affected with acute necrotizing encephalopathy (ANE) (PMID: 26923722, 27591117, 21945312, 20473521, 26110162). In some affected individuals it has been reported to be de novo (PMID: 19811512, 19118815). It has also been reported to segregate with ANE in multiple affected families (PMID: 19118815, 25128471, 25522933, 21205700, 19811512, 28336122). The penetrance of this variant is estimated to be 40% (PMID: 19118815). ClinVar contains an entry for this variant (Variation ID: 8363). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C). For these reasons, this variant has been classified as Pathogenic. 5

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

From Fulgent Genetics,Fulgent Genetics, SCV000893546.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Genomic Research Center,Shahid Beheshti University of Medical Sciences, SCV001251691.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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