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

gnomAD frequency: 0.00001  dbSNP: rs121434502

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000008868	SCV000767770	pathogenic	Familial acute necrotizing encephalopathy	2024-12-28	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	likely pathogenic	Familial acute necrotizing encephalopathy	2024-10-29	criteria provided, single submitter	clinical testing	A 5.5-year-old girl patient and her father were heterozygote for the variant NM_006267.5:c.1754C>T. The patient's father had no clinical symptoms related to RANBP2.
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	2024-02-22	criteria provided, single submitter	clinical testing	Not observed at 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	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 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