NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn) AND Osteopetrosis

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 23, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001251405.9

Allele description [Variation Report for NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn)]

NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn)

Gene:

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

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.2

Genomic location:

Preferred name:

NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn)

HGVS:

NC_000011.10:g.68047967G>A
NG_007878.1:g.13952G>A
NM_001351059.2:c.655G>A
NM_006019.4:c.1549G>AMANE SELECT
NM_006053.4:c.901G>A
NP_001337988.1:p.Asp219Asn
NP_006010.2:p.Asp517Asn
NP_006044.1:p.Asp301Asn
LRG_115:g.13952G>A
NC_000011.9:g.67815434G>A
NM_006019.3:c.1549G>A
p.Asp517Asn

Protein change:

D219N

Links:

dbSNP: rs369264588

NCBI 1000 Genomes Browser:

rs369264588

Molecular consequence:

NM_001351059.2:c.655G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006019.4:c.1549G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_006053.4:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Osteopetrosis
Identifiers:: MONDO: MONDO:0017198; MedGen: C0029454; Human Phenotype Ontology: HP:0011002

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Mus musculus immunity-related GTPase family M member 1 (Irgm1), transcript varia...
Mus musculus immunity-related GTPase family M member 1 (Irgm1), transcript variant 1, mRNA
gi|1247173967|ref|NM_008326.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001426994	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jul 23, 2020)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15300850, 31567691, 30898715 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001426994

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jul 23, 2020)

germline

clinical testing

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

Citation Link

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

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

TCIRG1 Transgenic Rescue of Osteoclast Function Using Induced Pluripotent Stem Cells Derived from Patients with Infantile Malignant Autosomal Recessive Osteopetrosis.

Chen W, Twaroski K, Eide C, Riddle MJ, Orchard PJ, Tolar J.

J Bone Joint Surg Am. 2019 Nov 6;101(21):1939-1947. doi: 10.2106/JBJS.19.00558.

PubMed [citation]

PMID:: 31567691

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001426994.1

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

Description

Variant summary: TCIRG1 c.1549G>A (p.Asp517Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250564 control chromosomes. c.1549G>A has been reported in the literature in individuals affected with Osteopetrosis (e.g. Susani_2004, Chen_2019). These data indicate that the variant may be associated with disease. At least one publication reports in vitro experimental evidence that osteoclasts derived from patient cells with this and another pathogenic variant in compound heterozygosity were impaired but functionality could be rescued by transgenic expression of TCIRG1 (Chen_2019). However, the individual contributions of these mutations to this phenotype were not assesed. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	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: Nov 3, 2024

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