Likely inborn error of metabolism

Gene: CLCN7

I don't know

Comment on list classification: Rating Amber as two individuals have been reported and with the same variant. Although there is some functional support, an additional independent case would help corroborate this association and indicate whether this is a variant specific phenotype. Different heterozygous CLCN7 variants have been linked to AD osteopetrosis.

Created: 21 Oct 2021, 11:01 a.m. | Last Modified: 21 Oct 2021, 11:01 a.m.

Panel Version: 1.76

Nicoli et al., 2019 (PMID: 31155284) reported on two unrelated individuals from different ethnic backgrounds with the same de novo gain-of-function missense variant (c.2144A>G, p.Tyr715Cys) in the CLCN7 gene. Both children had generalised cutaneous hypopigmentation without ocular involvement, delayed myelination and motor development, and organomegaly. Biopsies showed that both probands had cytoplasmic inclusions, characteristic of those seen in lysosomal-storage disorders. Human phenotypes were recapitulated by a mouse model harbouring the knock-in Clcn7 variant.

This gene-disease relationship is listed in OMIM (MIM# 618541) but is not yet in G2P.
Sources: Literature

Created: 21 Oct 2021, 10:48 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Hypopigmentation, organomegaly, and delayed myelination and development, OMIM:618541

Publications

• 31155284

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments