The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion (which was detected by chromosomal microarray). Most variants have been found to be private to a family, although the same amino acid (Leucine at position 221) has been mutated twice in two different families (p. Leu221Pro and p.Leu221Val), and the p.Gly544Arg variant has been detected in two different individuals, although due to a different nucleotide substitution in the two families.
Missense variants cluster within the helical trans or intermembrane domains of the protein, or the cystathionine-β-synthase (CBS) domain which is believed to be important for gating of the antiporter. All missense variants known to date that cluster in these regions have been shown to have a functional effect on electrophysiological studies when heterologously expressed in Xenopus oocytes.
All affected females to date have had a missense variant in CLCN4: heterozygous female carriers in families with predicted loss of function variants have essentially normal phenotypes.