Submissions for variant NM_006019.4(TCIRG1):c.702del (p.Ile235fs)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002789996	SCV003761313	likely pathogenic	Autosomal recessive osteopetrosis 1	2023-01-25	criteria provided, single submitter	curation	The homozygous p.Ile235SerfsTer44 variant in TCIRG1 was identified by our study in one individual with osteopetrosis. The p.Ile235SerfsTer44 variant in TCIRG1 has been previously reported in 3 individuals with autosomal recessive osteopetrosis 1 (PMID: 17400532, PMID: 15300850). These 3 affected individuals were homozygotes (PMID: 17400532, PMID: 15300850), which increases the likelihood that the p.Ile235SerfsTer44 variant is pathogenic. This variant was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 235 and leads to a premature termination codon 44 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the TCIRG1 gene is strongly associated to autosomal recessive osteopetrosis 1. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive osteopetrosis 1. ACMG/AMP Criteria applied: PVS1_Strong, PM2_Supporting, PM3 (Richards 2015).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002789996	SCV005087203	pathogenic	Autosomal recessive osteopetrosis 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive osteopetrosis 1 (MIM#259700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Patients may present with variable features (PMID: 17400532). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other variants predicted to cause NMD comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least three unrelated families with osteopetrosis (PMIDs: 15300850, 17400532). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign