ClinVar Genomic variation as it relates to human health

Observed as a single heterozygous variant in several individuals in published literature with milder symptoms of osteopetrosis (Frattini et al., 2003; Butscheidt et al., 2018; Wang et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; De novo variant with confirmed parentage in a patient referred for genetic testing at GeneDx; however, the reported clinical features are only partially consistent with the features typically observed in individuals with pathogenic variants in this gene; This variant is associated with the following publications: (PMID: 26365571, 30431110, 26659599, 21527911, 23983121, 33125761, 19953639, 35159175, 35370969, 32369273, 35309862, 26986070, 19288050, 29018903, 14584882, 11741829, 12929941, 16118345, 23443412)

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg286 amino acid residue in CLCN7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11741829, 17164308, 19543743, 21962762, 30942407, 31412925; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CLCN7 protein function. ClinVar contains an entry for this variant (Variation ID: 438670). This missense change has been observed in individuals with autosomal dominant osteopetrosis (PMID: 14584882, 32369273; Invitae). This variant has been reported in individual(s) with autosomal recessive osteopetrosis (PMID: 26365571); however, the role of the variant in this condition is currently unclear. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 286 of the CLCN7 protein (p.Arg286Gln).

The CLCN7 c.857G>A variant is predicted to result in the amino acid substitution p.Arg286Gln. This variant has been reported in the heterozygous state in multiple individuals with osteopetrosis (Table 3, Frattini et al. 2003. PubMed ID: 14584882; Table S1, Kosaki et al. 2020. PubMed ID: 32369273) and it has also been reported in the compound heterozygous state in an individual with infantile malignant osteopetrosis (Lin et al. 2015. PubMed ID: 26365571). This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD. An in vitro experimental study suggests this variant affects the activation kinetics of this channel protein (Figure 2, Ludwig et al. 2013. PubMed ID: 23983121). Alternate nucleotide changes affecting the same amino acid (p.Arg286Trp and p.Arg286Pro), have been reported in multiple individuals with osteopetrosis (see for example, Table 1, Cleiren et al. 2001. PubMed ID: 11741829; Table 2, Li et al. 2019. PubMed ID: 30942407; Yang et al. 2019. PubMed ID: 30431110). In summary, the c.857G>A (p.Arg286Gln) variant is interpreted as likely pathogenic.