Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480176 | SCV000568819 | likely pathogenic | not provided | 2017-03-01 | criteria provided, single submitter | clinical testing | The Y99C variant in the CLCN7 gene has been reported previously in the heterozygous state in several unrelated individuals with osteopetrosis, including two families with segregation in multiple affected individuals (Del Fattore et al., 2006; Zheng et al., 2016; Sui et al., 2013). In addition, Y99C was reported in the homozygous state in a male child with infantile malignant osteopetrosis (Barvencik et al., 2014). The Y99C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y99C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. The Y99C variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Ce |
RCV000480176 | SCV001247484 | pathogenic | not provided | 2019-08-01 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV000480176 | SCV002188231 | pathogenic | not provided | 2023-05-29 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. 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: 56890). This missense change has been observed in individuals with autosomal dominant osteopetrosis (PMID: 23296056, 26056022, 30229577). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 99 of the CLCN7 protein (p.Tyr99Cys). |
| Guangxi Key laboratory of Metabolic Diseases Research; Guilin 181st Hospital | RCV000050235 | SCV000082827 | probable-pathogenic | Autosomal dominant osteopetrosis 2 | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. | |
| Gene |
RCV000055847 | SCV000086843 | not provided | Autosomal recessive osteopetrosis 4 | no assertion provided | literature only |