ClinVar Miner

Submissions for variant NM_006019.4(TCIRG1):c.1213G>A (p.Gly405Arg)

gnomAD frequency: 0.00007  dbSNP: rs137853150
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000005796 SCV000791899 pathogenic Autosomal recessive osteopetrosis 1 2017-05-31 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000005796 SCV001369861 likely pathogenic Autosomal recessive osteopetrosis 1 2018-11-06 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP3,PP5.
Invitae RCV001390427 SCV001592159 pathogenic not provided 2024-01-24 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 405 of the TCIRG1 protein (p.Gly405Arg). This variant is present in population databases (rs137853150, gnomAD 0.04%). This missense change has been observed in individuals with osteopetrosis (PMID: 11532986, 12552563, 29363653). ClinVar contains an entry for this variant (Variation ID: 5463). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Molecular Lab, Department of Haematology, Christian Medical College RCV000005796 SCV002516046 pathogenic Autosomal recessive osteopetrosis 1 2022-05-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307355 SCV002600876 pathogenic Osteopetrosis 2022-10-04 criteria provided, single submitter clinical testing Variant summary: TCIRG1 c.1213G>A (p.Gly405Arg) results in a non-conservative amino acid change located in a highly conserved amino acid within a Transmembrane domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-05 in 250716 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TCIRG1 causing Osteopetrosis (7.2e-05 vs 0.0016), allowing no conclusion about variant significance. c.1213G>A has been reported in the literature in multiple individuals affected with Osteopetrosis (Sobacchi_2001, Cao_2018). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function in yeast (Ochotny_2006), finding that the variant results in reduced proton pump and ATPase activity. The variant is detected in trans with other known pathogenic variants (e.g. c.1331G>T, p.R444L), suggesting a pathogenic role. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity RCV000005796 SCV003813583 likely pathogenic Autosomal recessive osteopetrosis 1 2022-10-21 criteria provided, single submitter clinical testing
Baylor Genetics RCV000005796 SCV004205747 pathogenic Autosomal recessive osteopetrosis 1 2023-08-20 criteria provided, single submitter clinical testing
OMIM RCV000005796 SCV000025978 pathogenic Autosomal recessive osteopetrosis 1 2003-02-01 no assertion criteria provided literature only
Natera, Inc. RCV000005796 SCV002094910 pathogenic Autosomal recessive osteopetrosis 1 2021-10-11 no assertion criteria provided clinical testing

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