Submissions for variant NM_006019.4(TCIRG1):c.90C>T (p.Gly30=)

gnomAD frequency: 0.00162  dbSNP: rs141859450

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000393916	SCV000336503	uncertain significance	not provided	2015-10-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000765009	SCV000373693	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.
Fulgent Genetics, Fulgent Genetics	RCV000765009	SCV000896192	uncertain significance	Autosomal recessive osteopetrosis 1	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000393916	SCV001099504	likely benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000393916	SCV002544581	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	TCIRG1: PM2:Supporting, PP3
GeneDx	RCV000393916	SCV004170251	uncertain significance	not provided	2023-03-27	criteria provided, single submitter	clinical testing	In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Natera, Inc.	RCV000765009	SCV001458801	uncertain significance	Autosomal recessive osteopetrosis 1	2020-04-15	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000393916	SCV001549154	uncertain significance	not provided		no assertion criteria provided	clinical testing	The TCIRG1 p.Gly30Gly variant was not identified in the literature but was identified in dbSNP (ID: rs141859450) and ClinVar (classified as uncertain significance by EGL Genetics, Fulgent Genetics and Illumina). The variant was identified in control databases in 398 of 280570 chromosomes at a frequency of 0.001419 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 328 of 127460 chromosomes (freq: 0.002573), Other in 17 of 7166 chromosomes (freq: 0.002372), European (Finnish) in 31 of 24938 chromosomes (freq: 0.001243), Latino in 17 of 35400 chromosomes (freq: 0.00048), African in 3 of 24796 chromosomes (freq: 0.000121), Ashkenazi Jewish in 1 of 10290 chromosomes (freq: 0.000097) and South Asian in 1 of 30596 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Gly30Gly 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, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this has not been confirmed by RNA analysis and 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.