Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001251405 | SCV001426994 | likely pathogenic | Osteopetrosis | 2020-07-23 | criteria provided, single submitter | clinical testing | Variant summary: TCIRG1 c.1549G>A (p.Asp517Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250564 control chromosomes. c.1549G>A has been reported in the literature in individuals affected with Osteopetrosis (e.g. Susani_2004, Chen_2019). These data indicate that the variant may be associated with disease. At least one publication reports in vitro experimental evidence that osteoclasts derived from patient cells with this and another pathogenic variant in compound heterozygosity were impaired but functionality could be rescued by transgenic expression of TCIRG1 (Chen_2019). However, the individual contributions of these mutations to this phenotype were not assesed. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Molecular Diagnostics Laboratory, |
RCV001375862 | SCV001572790 | likely pathogenic | Autosomal recessive osteopetrosis 1 | 2021-01-28 | criteria provided, single submitter | clinical testing | |
| Kariminejad - |
RCV001814292 | SCV001755321 | likely pathogenic | Abnormality of the skeletal system | 2021-07-10 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002570450 | SCV003520647 | likely pathogenic | not provided | 2024-01-22 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 517 of the TCIRG1 protein (p.Asp517Asn). This variant is present in population databases (rs369264588, gnomAD 0.01%). This missense change has been observed in individuals with osteopetrosis (PMID: 15300850, 31567691). ClinVar contains an entry for this variant (Variation ID: 975009). 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 TCIRG1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Baylor Genetics | RCV001375862 | SCV004205755 | likely pathogenic | Autosomal recessive osteopetrosis 1 | 2024-03-27 | criteria provided, single submitter | clinical testing | |
| Natera, |
RCV001375862 | SCV002094919 | likely pathogenic | Autosomal recessive osteopetrosis 1 | 2020-10-14 | no assertion criteria provided | clinical testing |