ClinVar Miner

Submissions for variant NM_006019.4(TCIRG1):c.1372G>A (p.Gly458Ser)

gnomAD frequency: 0.00001  dbSNP: rs200851583
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669207 SCV000793937 uncertain significance Autosomal recessive osteopetrosis 1 2017-09-07 criteria provided, single submitter clinical testing
Invitae RCV001237832 SCV001410612 pathogenic not provided 2024-01-07 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 458 of the TCIRG1 protein (p.Gly458Ser). This variant is present in population databases (rs200851583, gnomAD 0.003%). This missense change has been observed in individual(s) with osteopetrosis (PMID: 28604959, 30539151, 30898715). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553699). 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 RCV000669207 SCV002516045 pathogenic Autosomal recessive osteopetrosis 1 2022-05-20 criteria provided, single submitter clinical testing
3billion RCV000669207 SCV002572945 likely pathogenic Autosomal recessive osteopetrosis 1 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TCIRG1-related disorder (ClinVar ID: VCV000553699 / PMID: 22231430). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 30539151). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Baylor Genetics RCV000669207 SCV004205769 pathogenic Autosomal recessive osteopetrosis 1 2023-06-29 criteria provided, single submitter clinical testing
Natera, Inc. RCV000669207 SCV002094913 likely pathogenic Autosomal recessive osteopetrosis 1 2020-09-21 no assertion criteria provided clinical testing

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