Albinism or congenital nystagmus

Gene: CLCN7

Green List (high evidence)

Comment on list classification: There are now 5 unrelated individuals (4 male, 1 female) with Hypopigmentation, organomegaly, and delayed myelination and development, harbouring heterozygous CLCN7 variants. 4/5 patients had confirmed de novo status. 2 different variants were reported, with p.Tyr715Cys recurring in 4 unrelated patients. Based on available evidence, CLCN7 should be promoted to Green on Albinism or congenital nystagmus.

Created: 5 Jun 2026, 3:32 p.m. | Last Modified: 5 Jun 2026, 3:32 p.m.

Panel Version: 4.8

PMID: 38838776 Polovitskaya et al., 2024
Report of unrelated male 2 individuals with hypopigmentation, muscular hypotonia, failure to thrive, organomegaly, delayed myelination, and psychomotor developmental disorder (no osteopetrosis), habrouring CLCN7 variants: p.Tyr715Cys (inheritance not confirmed) and p.Lys285Thr (de novo).
Patient fibroblast studies showed that both disease-associated mutations affect the inhibition of ClC-7 by PI(3,5)P2 and shift its voltage-dependent gating to more physiological lysosomal voltages.

PMID: 39056574 Lee et al., 2024
Report of a Taiwanese boy presenting with significant developmental delay, organomegaly, hypogammaglobulinemia and hypopigmentation (generalized hypopigmentation of the skin, hair, and ocular albinism that had been present since birth) without osteopetrosis. WES revealed a de novo GOF variant, p.Tyr715Cys in CLCN7.

Created: 5 Jun 2026, 3:32 p.m. | Last Modified: 5 Jun 2026, 3:32 p.m.

Panel Version: 4.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

• 38838776
• 39056574

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: 1.19

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