Submissions for variant NM_006019.4(TCIRG1):c.2445C>T (p.Gly815=)

gnomAD frequency: 0.00022  dbSNP: rs150788130

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000381461	SCV000342256	uncertain significance	not provided	2016-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000381461	SCV000891982	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	TCIRG1: BP4, BP7
Invitae	RCV000381461	SCV001106097	likely benign	not provided	2024-01-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001113576	SCV001271360	uncertain significance	Autosomal recessive osteopetrosis 1	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Natera, Inc.	RCV001113576	SCV001452921	uncertain significance	Autosomal recessive osteopetrosis 1	2020-01-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000381461	SCV001552368	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TCIRG1 p.Gly599Gly variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs150788130) and in ClinVar (classified as a VUS by EGL Genetics and Praxis fuer Humangenetik Tuebingen). The variant was also identified in control databases in 91 of 282564 chromosomes (1 homozygous) at a frequency of 0.000322 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: Other in 9 of 7222 chromosomes (freq: 0.001246), European (Finnish) in 18 of 24946 chromosomes (freq: 0.000722), Latino in 21 of 35430 chromosomes (freq: 0.000593), European (non-Finnish) in 35 of 129092 chromosomes (freq: 0.000271), African in 6 of 24946 chromosomes (freq: 0.000241), Ashkenazi Jewish in 1 of 10364 chromosomes (freq: 0.000096) and East Asian in 1 of 19948 chromosomes (freq: 0.00005), while the variant was not observed in the South Asian population. The p.Gly599Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, 3 of 4 in silico or computational prediction software programs, (MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a new 5' splice site; 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.