CNNM2

Inheritance Pattern: AR

Disease ID:MONDO:0020787

Submitter: G2P

Inheritance Pattern: AD

Disease ID:MONDO:0020787

Submitter: Illumina

The CNNM2 gene is located on chromosome 10 at 10q24.32 and encodes the cyclin and CBS domain divalent metal cation transport mediator 2 protein. This protein shows high basolateral expression in the renal tubule segments most involved in magnesium resorption and is also expressed in the brain (21397062: Stuiver et al. 2011). Functional studies suggest it acts to regulate magnesium transport (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). CNNM2 was first reported in relation to CNNM2-related hypomagnesemia, seizures and intellectual disability, autosomal dominant, in 2011 (21397062: Stuiver et al. 2011). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least five probands in two publications (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). Three cases carried CNNM2 variants in a heterozygous state, variants occurred de novo in three of these cases. Of the five unique variants, four were missense and one resulted in a frameshift variant and predicted loss of function. Evaluation of the missense variants in vitro indicates a loss of function or hypomorphic mechanism of disease. This gene-disease relationship is supported by experimental data including a zebrafish, CNNM2 morpholino knockdown model which recapitulated the key features of disease, demonstrating a gene dosage dependant reduction in magnesium levels, brain malformation, and signs of neuromuscular impairment. These phenotypes were exacerbated by expression of mutant CNNM2 and rescued by expression of wildtype CNNM2 (24699222: Arjona et al. 2014). Additional experimental support comes from expression studies and in vitro functional assays (21397062: Stuiver et al. 2011; 24699222: Arjona et al. 2014). In summary, there is strong evidence to support the relationship between CNNM2 and autosomal dominant CNNM2-related hypomagnesemia, seizures and intellectual disability. Additional clinical reports are needed to reach a definitive classification.

Inheritance Pattern: SD

Disease ID:MONDO:0020787

Submitter: ClinGen

The *CNNM2* gene is located on chromosome 10 at q24.32 and encodes the cyclin and CBS domain divalent metal cation transport mediator 2. *CNNM2* mediates transport of divalent metal cations, specifically Mg2+. It is expressed throughout the kidney, with specific expression in the thick ascending limb (TAL) of Henle's loop and the distal convoluted tubule (DCT). Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: renal hypomagnesemia 6 (OMIM:613882) and hypomagnesemia, seizures, and impaired intellectual development 1 (OMIM:616418). The preferred disease name suggested for this grouping of disorders is hypomagnesemia with or without seizures and intellectual disability. *CNNM2* was first reported in relation to semi-dominant hypomagnesemia with or without seizures and intellectual disability in 2011 (Stuiver et al., PMID: 21397062). The mechanism of pathogenicity is known to be loss of function. Patients with this disorder present with hypomagnesemia, sometimes with variable seizures and/or intellectual disability among other syndromic disorders more frequently seen in more severe biallelic homozygous or compound heterozygous cases. Fourteen variants (missense, in-frame indel, nonsense, frameshift) have been reported in 14 probands in 4 publications (PMIDs: 21397062, 24699222, 30026055, 33600043 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by expression studies, in vitro assays in non-patient cells, and animal models. Immunohistochemistry on human kidney sections revealed that *CNNM2* is expressed in both the TAL of Henle's loop, as indicated by and the DCT (PMID: 21397062). Additionally, where wildtype HEK293 cells showed increased Mg2+ uptake, HEK293 cells expressing mutated *CNNM2* proteins did not, demonstrating a causative mechanism of hypomagnesemia (PMID: 24699222). Furthermore, knockdown of *CNNM2* orthologues in zebrafish results in impaired development of the brain, abnormal neurodevelopmental phenotypes manifesting as altered locomotor and touch-evoke escape behaviours, and reduced body Mg content, indicative of impaired renal Mg2+ absorption (PMID: 24699222). Finally, homozygous and heterozygous *Cnnm2* knock out mice presented with hypomagnesemia (PMID: 33600043). A total of 5/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CNNM2* and semi-dominant hypomagnesemia with or without seizures and intellectual disability. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date February 15, 2024 (SOP Version 10.1).

Inheritance Pattern: AD

Disease ID:MONDO:0013480

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0020787

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0020787

Submitter: G2P