Submissions for variant NM_002224.4(ITPR3):c.7570C>T (p.Arg2524Cys)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CUBI - Core Unit Bioinformatics, Berlin Institute of Health	RCV003330107	SCV004037107	likely pathogenic	not provided		criteria provided, single submitter	not provided
Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	RCV003330107	SCV004037115	likely pathogenic	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003408224	SCV004108522	likely pathogenic	ITPR3-related disorder	2023-05-19	criteria provided, single submitter	clinical testing	The ITPR3 c.7570C>T variant is predicted to result in the amino acid substitution p.Arg2524Cys. This variant has been documented as de novo in a patient with childhood onset Charcot-Marie-Tooth disease (CMT) (Patient P5 in Rönkkö et al 2020. PubMed ID: 32949214) and in the compound heterozygous state in a patient presenting with combined immunodeficiency and CMT (Patient P1 in Neumann et al. 2022. PubMed ID: 36302985). Functional studies of fibroblasts isolated from the patient described in Neumann et al. showed a disruption of channel function and calcium signaling. However, due to the compound heterozygous finding in this patient, analysis of the individual contribution of p.Arg2524Cys to the biological defect was not examined (Neumann et al. 2022. PubMed ID: 36302985). An additional functional analysis of the p.Arg2524Cys variant within a cell line lacking other endogenous IP3R isoforms and ITPR3 variants showed that the protein was non-functional (Terry et al. 2022. PubMed ID: 36444295). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
OMIM	RCV002305678	SCV002599088	pathogenic	Charcot-Marie-Tooth disease, demyelinating, type 1J	2022-11-03	no assertion criteria provided	literature only
Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	RCV002305678	SCV004037367	uncertain significance	Charcot-Marie-Tooth disease, demyelinating, type 1J	2020-11-05	flagged submission	clinical testing	The c.7570C>T variant is a single basepair substitution in exon 55 of 58 of the ITPR3 gene, which causes a substitution of the highly conserved arginine to cysteine at position 2524 (2524 of 2672) in the channel pore of transmembrane domain. Pathogenic variants localized in the channel pore of this transmembrane are predicted to affect the channel properties and/or the ion flux directly [PMID:32949214]. In silico analysis (including PolyPhen-2, SIFT and PROVEAN) consistently predict this variant to have a damaging effect on protein structure and/or function. This variant has not been observed in the Genome Aggregation Database (gnomAD) and is absent from ClinVar. [accessed 10/20/2020] ITPR3 encodes inositol 1,4,5-triphosphate receptor, type 3 which is involved in the mobilization of intracellular calcium [MIM#147267] The ITPR3 gene has not been reported to be associated with Mendelian disease in the OMIM database (accessed 10/20/2020). However, several articles have reported missense variants in this gene in cohorts of patients with Charcot-Marie-Tooth disease and hereditary sensory motor neuropathy (PMIDs: 27549087;24627108, 32949214).