NM_006019.4(TCIRG1):c.702del (p.Ile235fs) AND Autosomal recessive osteopetrosis 1

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jul 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV002789996.4

Allele description [Variation Report for NM_006019.4(TCIRG1):c.702del (p.Ile235fs)]

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

Gene:

TCIRG1:T cell immune regulator 1, ATPase H+ transporting V0 subunit a3 [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

11q13.2

Genomic location:

Preferred name:

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

Other names:

NM_006053.4:c.54del

HGVS:

NC_000011.10:g.68043642del
NG_007878.1:g.9627del
NM_001351059.2:c.-209del
NM_006019.3:c.702delG
NM_006019.4:c.702delMANE SELECT
NM_006053.4:c.54del
NP_006010.2:p.Ile235Serfs
NP_006010.2:p.Ile235fs
NP_006044.1:p.Ile19fs
LRG_115t1:c.702del
LRG_115:g.9627del
LRG_115p1:p.Ile235Serfs
NC_000011.9:g.67811109del
NM_006019.2:c.702delG

Protein change:

I19fs

Links:

dbSNP: rs2495622382

NCBI 1000 Genomes Browser:

rs2495622382

Molecular consequence:

NM_001351059.2:c.-209del - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_006019.4:c.702del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_006053.4:c.54del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Autosomal recessive osteopetrosis 1
Synonyms:: ALBERS-SCHONBERG DISEASE, AUTOSOMAL RECESSIVE; TCIRG1-Related Autosomal Recessive Osteopetrosis
Identifiers:: MONDO: MONDO:0009815; MedGen: C1850127; Orphanet: 667; OMIM: 259700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003761313	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Jan 25, 2023)	germline	curation	PubMed (1) [See all records that cite this PMID]
SCV005087203	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 17, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15300850, 17400532, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003761313

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Jan 25, 2023)

germline

curation

PubMed (1)
[See all records that cite this PMID]

SCV005087203

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 17, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

TCIRG1-dependent recessive osteopetrosis: mutation analysis, functional identification of the splicing defects, and in vitro rescue by U1 snRNA.

Susani L, Pangrazio A, Sobacchi C, Taranta A, Mortier G, Savarirayan R, Villa A, Orchard P, Vezzoni P, Albertini A, Frattini A, Pagani F.

Hum Mutat. 2004 Sep;24(3):225-35.

PubMed [citation]

PMID:: 15300850

Molecular study of six families originating from the Middle-East and presenting with autosomal recessive osteopetrosis.

Souraty N, Noun P, Djambas-Khayat C, Chouery E, Pangrazio A, Villa A, Lefranc G, Frattini A, Mégarbané A.

Eur J Med Genet. 2007 May-Jun;50(3):188-99. Epub 2007 Feb 21.

PubMed [citation]

PMID:: 17400532

See all PubMed Citations (3)

Details of each submission

From Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV003761313.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

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‚Äôs 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005087203.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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