Submissions for variant NM_006019.4(TCIRG1):c.1249G>A (p.Ala417Thr)

gnomAD frequency: 0.00275  dbSNP: rs140963213

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224875	SCV000281481	uncertain significance	not provided	2016-01-21	criteria provided, single submitter	clinical testing	Converted during submission to Uncertain significance.
Fulgent Genetics, Fulgent Genetics	RCV000509143	SCV000896193	uncertain significance	Autosomal recessive osteopetrosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Invitae	RCV000224875	SCV001101374	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000509143	SCV001269765	uncertain significance	Autosomal recessive osteopetrosis 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000224875	SCV001815537	uncertain significance	not provided	2023-05-18	criteria provided, single submitter	clinical testing	Reported with another TCIRG1 variant in two families with osteopetrosis in published literature (Afshariyamchlou et al., 2022; Jaber et al., 2022); Reported in an additional patient in published literature with severe osteopetrosis; however, further information such as zygosity or presence of another variant was not provided (Pangrazio et al., 2012); Reported in published literature in association with other phenotypes, including lower absolute neutrophil count and risk for glioma, but additional research is needed to explore a possible link between TCIRG1 variants and these phenotypes (Rosenthal et al., 2016; Kinnersley et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34426522, 33206719, 26264438, 27229898, 35573728, 35802155, 35720663, 22231430)
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277583	SCV002564686	uncertain significance	Increased bone mineral density	2018-12-01	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224875	SCV004137064	likely benign	not provided	2023-05-01	criteria provided, single submitter	clinical testing	TCIRG1: BS2
GenomeConnect, ClinGen	RCV000509143	SCV000607184	not provided	Autosomal recessive osteopetrosis 1		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Natera, Inc.	RCV000509143	SCV001462937	benign	Autosomal recessive osteopetrosis 1	2020-01-08	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000224875	SCV001548832	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TCIRG1 p.Ala201Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs140963213) and in ClinVar (classified as a VUS by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics and Fulgent Genetics for Osteopetrosis autosomal recessive 1). The variant was identified in control databases in 727 of 282162 chromosomes (2 homozygous) at a frequency of 0.002577 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 548 of 128706 chromosomes (freq: 0.004258), Ashkenazi Jewish in 26 of 10332 chromosomes (freq: 0.002516), Latino in 84 of 35396 chromosomes (freq: 0.002373), Other in 15 of 7212 chromosomes (freq: 0.00208), European (Finnish) in 25 of 25086 chromosomes (freq: 0.000997), African in 22 of 24876 chromosomes (freq: 0.000884), South Asian in 6 of 30616 chromosomes (freq: 0.000196) and East Asian in 1 of 19938 chromosomes (freq: 0.00005). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Ala201 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224875	SCV001971766	uncertain significance	not provided		no assertion criteria provided	clinical testing