NM_006019.4(TCIRG1):c.1674-1G>A AND Autosomal recessive osteopetrosis 1

Germline classification:: Pathogenic (10 submissions)
Last evaluated:: Feb 23, 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:: RCV000169678.22

Allele description [Variation Report for NM_006019.4(TCIRG1):c.1674-1G>A]

NM_006019.4(TCIRG1):c.1674-1G>A

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.1674-1G>A

HGVS:

NC_000011.10:g.68049080G>A
NG_007878.1:g.15065G>A
NM_001351059.2:c.780-1G>A
NM_006019.4:c.1674-1G>AMANE SELECT
NM_006053.4:c.1026-1G>A
LRG_115:g.15065G>A
NC_000011.9:g.67816547G>A
NM_006019.3:c.1674-1G>A

Links:

dbSNP: rs139617644

NCBI 1000 Genomes Browser:

rs139617644

Molecular consequence:

NM_001351059.2:c.780-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_006019.4:c.1674-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]
NM_006053.4:c.1026-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]

Observations:

Condition(s)

Name:: Autosomal recessive osteopetrosis 1
Synonyms:: ALBERS-SCHONBERG DISEASE, AUTOSOMAL RECESSIVE; Osteopetrosis infantile malignant 1; Marble bones autosomal recessive
Identifiers:: MONDO: MONDO:0009815; MedGen: C1850127; Orphanet: 667; OMIM: 259700

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CREBBP CREB binding protein [Homo sapiens]
CREBBP CREB binding protein [Homo sapiens]
Gene ID:1387

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000221216	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq	criteria provided, single submitter (LMM Criteria)	Pathogenic (Jan 15, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10888887, 24033266
SCV000893228	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000914535	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Pathogenic (Aug 22, 2018)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 11532986, 15300850, 10888887 Citation Link,
SCV001193994	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Women's Health Autosomal Recessive and X-Linked Classification Criteria (2021))	Pathogenic (Oct 1, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV001456352	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001521802	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 20, 2020)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002073777	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 10888887, 11532986, 15300850, 25741868
SCV002073897	Genomics Facility, Ludwig-Maximilians-Universität München	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 28, 2021)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25741868, 10888887, 19507210
SCV003827984	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003841447	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2023)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10888887, 25741868

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
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	1	1	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

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

See all PubMed Citations (6)

PMC

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL.

Genetics in medicine : official journal of the American College of Medical Genetics. 2015 Mar 5; 17(5): 405-424

PMC [article]

PMCID:: PMC4544753
PMID:: 25741868
DOI:: 10.1038/gim.2015.30

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine - CSER-MedSeq, SCV000221216.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

The c.1674-1G>A variant in TCIRG1 has been reported in 3 unrelated patients affected with autosomal recessive infantile malignant osteopetrosis. Two of the patients were compound heterozygotes and one was homozygous (Frattini 2000). The variant has further been identified in 0.02% (2/8588) of European American chromosomes and 0.02% (1/4400) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant occurs in the invariant region (+/- 1/2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).

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

From Fulgent Genetics, Fulgent Genetics, SCV000893228.2

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

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

From Illumina Laboratory Services, Illumina, SCV000914535.1

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

Description

The TCIRG1 c.1674-1G>A variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.1674-1G>A variant has been reported in three studies in which it is found in a total of 14 individuals with osteopetrosis including at least three homozygotes and 11 compound heterozygotes (Frattini et al. 2000; Sobacchi et al. 2001; Susani et al. 2004). The c.1674-1G>A variant was absent from 520 control chromosomes and is reported at a frequency of 0.000316 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies using RT-PCR revealed that the c.1674-1G>A variant causes abnormal splicing of the TCIRG1 transcript which was not detected in normal controls (Frattini et al. 2000). Western blot analysis of the cell lysates from two compound heterozygotes did not detect the presence of any TCIRG1 protein (Frattini et al. 2000). Based on the collective evidence and potential impact of splice site variants, the c.1674-1G>A is classified as pathogenic for osteopetrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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 Myriad Genetics, Inc., SCV001193994.3

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

Description

NM_006019.3(TCIRG1):c.1674-1G>A is a canonical splice variant classified as pathogenic in the context of autosomal recessive osteopetrosis type 1. c.1674-1G>A has been observed in cases with relevant disease (PMID: 15300850). Functional assessments of this variant are not available in the literature. c.1674-1G>A has been observed in population frequency databases (gnomAD: NFE 0.03%). In summary, NM_006019.3(TCIRG1):c.1674-1G>A is a variant in a canonical splice site in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.

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

From Natera, Inc., SCV001456352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	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 Baylor Genetics, SCV001521802.1

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

Description

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].

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

From DASA, SCV002073777.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (4)

Description

The c.1674-1G>A variant is located in a canonical splice-site, and it is predicted to alter gene function due to either exon skipping or nonsense-mediate decay – NMD, and the variant is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189246; PMID: 10888887; 11532986; 15300850) - PS4. The variant is present at low allele frequencies population databases (rs139617644 – gnomAD 0.001839%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The c.1674-1G>A was detected in trans with a pathogenic variant (PMID: 10888887) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic.

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

From Genomics Facility, Ludwig-Maximilians-Universität München, SCV002073897.1

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

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

From Revvity Omics, Revvity, SCV003827984.2

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

#	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 3billion, SCV003841447.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.016%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000189246 / PMID: 10888887). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: May 26, 2024

Relating variation to medicine