Renal tubulopathies
Gene: CNNM2
The rating of this gene has been updated to Green and the mode of inheritance set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.Created: 31 Jan 2023, 12:39 p.m. | Last Modified: 31 Jan 2023, 12:39 p.m.
Panel Version: 3.3
Comment on list classification: Promoting this gene from grey to amber but with a recommendation of GREEN rating following GMS review. Many monoallelic cases reported plus 2 biallelic.Created: 2 Aug 2022, 10:13 p.m. | Last Modified: 2 Aug 2022, 10:13 p.m.
Panel Version: 2.59
Comment on mode of pathogenicity: There is a mix of missense and truncating variants reported.Created: 2 Aug 2022, 10:10 p.m. | Last Modified: 2 Aug 2022, 10:10 p.m.
Panel Version: 2.56
Associated with Hypomagnesemia 6, renal #613882 (AD) and Hypomagnesemia, seizures, and mental retardation #616418 (AD, AR) in OMIM.
Many reports of heterozygous variants (de novo or dominant inheritance) in CNNM2 in individuals with hypomagnesemia with or without seizure and intellectual disability. Variants include missense, nonsense, in-frame deletions and large deletions.
PMID: 33600043 - Franken et al 2021 - report 11 novel variants in CNNM2 were identified in nine single sporadic cases and in two families with hypomagnesemia. Variants consisted of 6 missense, 2 nonsense mutations, two large deletions, and one in‐frame single amino acid deletion. 8 were de de novo.
PMID:34604137 - Zhang et al 2021 - report 2 unrelated cases of Chinese children with de novo missense variants in CNNM2 and a phenotype of infantile-onset epilepsy with DD and hypomagnesemia refractory to magnesium supplementation.
PMID: 33859252 - Franken et al 2021 - CNNM2 knockout mice show mild hypomagnesaemia and developmental defects
PMID: 35002148 - Panda et al 2021 - a 4-month-old girl with West Syndrome (hypomagnesemia, developmental delay and epileptic spasms) caused by de novo heterozygous missense variant (c.82G>A, (p.Ala28Thr)) in the CNNM2 gene.
PMID: 21397062 - Stuiver et al 2011 - in two unrelated families with dominant hypomagnesemia (from the Netherlands and Czech Republic) they identified heterozygous variants in CNNM2 after sequencing CNNM2 and 3 other candidate genes; c.117delG (p.Ile40SerfsX15) and c.1703C>T (p.Thr568Ile). The missense mutation significantly impairs CNNM2 function.
PMID:32997713 - García-Castaño et al 2020 - report 1 patient with a suspected disorder of calcium metabolism and hypomagnesemia who was found to have a likely pathogenic heterozygous truncating variant in CNNM2. No intellectual disability was observed. 3 other patients with missense variants classified as VUS in CNNM2 are also described (1 with disorder of calcium metabolism and 2 with primary tubulopathy).
2 families with probands with homozygous variants and a more severe phenotype are also reported:
PMID:30026055 - Andrea Accogli et al 2019 - report a homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy/intellectual disability. The asymptomatic parents were not sequenced, but two other siblings had died in infancy.
PMID:24699222 - Arjona et al 2014 - five unrelated families suffering from a distinct phenotype of mental retardation, seizures and hypomagnesemia. In 4 families the affected individuals had heterozygous misssense variants in CNNM2, 1 family with 2 siblings with severe intellectual disability with homozygous missense variants inherited from the unaffected parents.Created: 2 Aug 2022, 10:09 p.m. | Last Modified: 2 Aug 2022, 10:09 p.m.
Panel Version: 2.54
Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes
Hypomagnesemia 6, renal, OMIM:613882; Hypomagnesemia, seizures, and mental retardation, OMIM:616418; renal hypomagnesemia 6, MONDO:0013480
described with dominant and recessive inheritance (associated with phenotype severity), but mostly with heterozygous de novo variants
Sources: Expert listCreated: 31 May 2022, 3:33 p.m.
Mode of inheritance
Other
Phenotypes
hypomagnesaemia; seizures; intellectual disability
Publications
Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Tag Q3_22_rating was removed from gene: CNNM2. Tag Q3_22_MOI was removed from gene: CNNM2. Tag Q3_22_NHS_review was removed from gene: CNNM2.
Source Expert Review Green was added to CNNM2. Source NHS GMS was added to CNNM2. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Gene: cnnm2 has been classified as Amber List (Moderate Evidence).
Tag Q3_22_rating tag was added to gene: CNNM2. Tag Q3_22_MOI tag was added to gene: CNNM2. Tag Q3_22_NHS_review tag was added to gene: CNNM2.
Phenotypes for gene: CNNM2 were changed from hypomagnesaemia; seizures; intellectual disability to Hypomagnesemia 6, renal, OMIM:613882; Hypomagnesemia, seizures, and mental retardation, OMIM:616418; renal hypomagnesemia 6, MONDO:0013480; Hypomagnesemia, seizures, and mental retardation, MONDO:0014631
Publications for gene: CNNM2 were set to PMID: 33600043; 30026055; 32997713; 34604137; 33859252; 24699222; 35002148; 21397062
Mode of pathogenicity for gene: CNNM2 was changed from Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments to Other
Mode of inheritance for gene: CNNM2 was changed from Other to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
gene: CNNM2 was added gene: CNNM2 was added to Renal tubulopathies. Sources: Expert list Mode of inheritance for gene: CNNM2 was set to Other Publications for gene: CNNM2 were set to PMID: 33600043; 30026055; 32997713; 34604137; 33859252; 24699222; 35002148; 21397062 Phenotypes for gene: CNNM2 were set to hypomagnesaemia; seizures; intellectual disability Penetrance for gene: CNNM2 were set to Complete Mode of pathogenicity for gene: CNNM2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: CNNM2 was set to GREEN