ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs121434502
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000008868 SCV000767770 pathogenic Familial acute necrotizing encephalopathy 2023-10-09 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 585 of the RANBP2 protein (p.Thr585Met). This variant is present in population databases (rs121434502, gnomAD no frequency). This missense change has been observed in individual(s) with acute necrotizing encephalopathy (ANE) (PMID: 19118815, 19811512, 20473521, 21205700, 21945312, 25128471, 25522933, 26110162, 26923722, 27591117, 28336122). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8363). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics RCV000008868 SCV000893546 pathogenic Familial acute necrotizing encephalopathy 2018-10-31 criteria provided, single submitter clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences RCV000008868 SCV001251691 uncertain significance Familial acute necrotizing encephalopathy 2020-05-03 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV001291580 SCV001480116 likely pathogenic not provided 2021-02-01 criteria provided, single submitter clinical testing
GeneDx RCV001291580 SCV001764260 pathogenic not provided 2022-11-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21205700, 20473521, 29741717, 34377735, 33879512, 24321870, 25128471, 26923722, 27591117, 19811512, 21945312, 28336122, 25522933, 30796099, 29687329, 31589614, 33726816, 32760653, 34059398, 19118815, 34400285, 33777149, 33761695)
Suma Genomics RCV000008868 SCV003762227 likely pathogenic Familial acute necrotizing encephalopathy criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000008868 SCV003921869 pathogenic Familial acute necrotizing encephalopathy 2022-02-23 criteria provided, single submitter clinical testing 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Asymptomatic carriers are well-reported in the literature (PMID: 19118815, 30796099). Penetrance was estimated at 40% in one large family (PMID: 19118815). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (1 heterozygotes, 0 homozygotes). (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The p.(Thr585Met) variant is recurrent in individuals with acute infection-induced encephalopathy, and has been reported de novo and in families with incomplete penetrance (ClinVar, PMID: 19118815, 30796099, 27591117). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, University Hospital Muenster RCV003231094 SCV003929500 likely pathogenic See cases 2023-02-28 criteria provided, single submitter clinical testing ACMG categories: PS4,PM2,PP5,BP4
Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital RCV000008868 SCV003935140 likely pathogenic Familial acute necrotizing encephalopathy 2023-06-24 criteria provided, single submitter clinical testing This variant has been identified in a proband with acute necrotizing encephalopathy. The phenotype observed in the proband was encephalopathy and seizures after febrile illness. This variant has also been segregated in the mother. This variant is not found in gnomAD (PM2_moderate). This variant has been previously reported PMID: 32760653 (PP5_very strong). PMID 19811512 has reported the presence of a heterozygous c.1880C>T in mother as well as the proband and the encephalopathy was triggered post a viral infection or illness.
OMIM RCV000008868 SCV000029078 risk factor Familial acute necrotizing encephalopathy 2011-01-04 no assertion criteria provided literature only
GeneReviews RCV000008868 SCV000212035 not provided Familial acute necrotizing encephalopathy no assertion provided literature only
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000008868 SCV000734136 pathogenic Familial acute necrotizing encephalopathy no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV001291580 SCV001809103 pathogenic not provided no assertion criteria provided clinical testing

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