NM_006019.4(TCIRG1):c.1331G>T (p.Arg444Leu) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 20, 2023
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:: RCV003555929.3

Allele description [Variation Report for NM_006019.4(TCIRG1):c.1331G>T (p.Arg444Leu)]

NM_006019.4(TCIRG1):c.1331G>T (p.Arg444Leu)

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.1331G>T (p.Arg444Leu)

HGVS:

NC_000011.10:g.68047672G>T
NG_007878.1:g.13657G>T
NM_001351059.2:c.437G>T
NM_006019.4:c.1331G>TMANE SELECT
NM_006053.4:c.683G>T
NP_001337988.1:p.Arg146Leu
NP_006010.2:p.Arg444Leu
NP_006044.1:p.Arg228Leu
LRG_115:g.13657G>T
NC_000011.9:g.67815139G>T
Q13488:p.Arg444Leu

Protein change:

R146L; ARG444LEU

Links:

UniProtKB: Q13488#VAR_019570; OMIM: 604592.0006; dbSNP: rs137853151

NCBI 1000 Genomes Browser:

rs137853151

Molecular consequence:

NM_001351059.2:c.437G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006019.4:c.1331G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_006053.4:c.683G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004294900	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 20, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11532986, 22685294, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004294900

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 20, 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

Citations

PubMed

The mutational spectrum of human malignant autosomal recessive osteopetrosis.

Sobacchi C, Frattini A, Orchard P, Porras O, Tezcan I, Andolina M, Babul-Hirji R, Baric I, Canham N, Chitayat D, Dupuis-Girod S, Ellis I, Etzioni A, Fasth A, Fisher A, Gerritsen B, Gulino V, Horwitz E, Klamroth V, Lanino E, Mirolo M, Musio A, et al.

Hum Mol Genet. 2001 Aug 15;10(17):1767-73.

PubMed [citation]

PMID:: 11532986

Osteopetrosis mutation R444L causes endoplasmic reticulum retention and misprocessing of vacuolar H+-ATPase a3 subunit.

Bhargava A, Voronov I, Wang Y, Glogauer M, Kartner N, Manolson MF.

J Biol Chem. 2012 Aug 3;287(32):26829-39. doi: 10.1074/jbc.M112.345702. Epub 2012 Jun 8.

PubMed [citation]

PMID:: 22685294
PMCID:: PMC3411020

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004294900.2

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

Description

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TCIRG1 protein function. ClinVar contains an entry for this variant (Variation ID: 5464). This missense change has been observed in individuals with infantile malignant osteopetrosis (PMID: 11532986). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TCIRG1 function (PMID: 22685294). This variant is present in population databases (rs137853151, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 444 of the TCIRG1 protein (p.Arg444Leu).

#	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: Apr 7, 2025

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