VCV000005443.30 - ClinVar

NM_005149.3(TBX19):c.782del (p.Asn261fs)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005149.3(TBX19):c.782del (p.Asn261fs)

Variation ID: 5443 Accession: VCV000005443.30

Type and length

Deletion, 1 bp

Location

Cytogenetic: 1q24.2 1: 168305061 (GRCh38) [ NCBI UCSC ] 1: 168274299 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Oct 20, 2024	Jul 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005149.3:c.782del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005140.1:p.Asn261fs	frameshift
NC_000001.11:g.168305062del
NC_000001.10:g.168274300del
NG_008244.1:g.29023del

Protein change

N261fs

Other names

Canonical SPDI

NC_000001.11:168305060:AA:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA250033 OMIM: 604614.0004 dbSNP: rs730880274 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
TBX19		-	-	GRCh38 GRCh37	163	183

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Congenital isolated adrenocorticotropic hormone deficiency	Pathogenic (3)	criteria provided, single submitter	Apr 6, 2022	RCV000005776.6
not provided	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000362203.23
TBX19-related disorder	Pathogenic (1)	criteria provided, single submitter	Apr 3, 2023	RCV003415661.4

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Apr 06, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital isolated adrenocorticotropic hormone deficiency Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002511704.1 First in ClinVar: May 16, 2022 Last updated: May 16, 2022	Publications: PubMed (3) PubMed: 15476446‚ 12651888‚ 15613420 Comment: Variant summary: TBX19 c.782delA (p.Asn261IlefsX46) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more) Variant summary: TBX19 c.782delA (p.Asn261IlefsX46) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251390 control chromosomes. c.782delA has been reported in the literature in multiple individuals affected with Adrenocorticotropic Hormone Deficiency in the homozyous and compound heterozyous state (Metherell_2004, Vallette-Kasic_2005, Pulichino_2003). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Apr 03, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	TBX19-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004115563.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The TBX19 c.782delA variant is predicted to result in a frameshift and premature protein termination (p.Asn261Ilefs46). This variant has been reported in patients with isolated … (more) The TBX19 c.782delA variant is predicted to result in a frameshift and premature protein termination (p.Asn261Ilefs46). This variant has been reported in patients with isolated ACTH deficiency (Pulichino et al. 2003. PubMed ID: 12651888; Jullien et al. 2020. PubMed ID: 33098107). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-168274298-CA-C). Frameshift variants in TBX19 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
Pathogenic (Apr 05, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000330040.5 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Comment: The c.782delA pathogenic variant in the TBX19 gene has been reported previously in association with isolated ACTH deficiency (Metherell et al., 2004). The c.782delA variant … (more) The c.782delA pathogenic variant in the TBX19 gene has been reported previously in association with isolated ACTH deficiency (Metherell et al., 2004). The c.782delA variant causes a frameshift starting with codon Asparagine 261, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 46 of the new reading frame, denoted p.Asn261IlefsX46. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.782delA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.782delA as apathogenic variant. (less)
Pathogenic (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001246095.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Comment: TBX19: PVS1, PM3:Strong, PM2 Number of individuals with the variant: 2
Pathogenic (Oct 01, 2004)	no assertion criteria provided Method: literature only	ACTH DEFICIENCY, ISOLATED Affected status: not provided Allele origin: germline	OMIM Accession: SCV000025958.3 First in ClinVar: Apr 04, 2013 Last updated: Mar 11, 2018	Publications: PubMed (1) PubMed: 15476446 Comment on evidence: For discussion of the 1-bp deletion in the TBX19 gene (782delA) that was found in compound heterozygous state in patients with early-onset ACTH deficiency (IAD; … (more) For discussion of the 1-bp deletion in the TBX19 gene (782delA) that was found in compound heterozygous state in patients with early-onset ACTH deficiency (IAD; 201400) by Metherell et al. (2004), see 604614.0003. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963170.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001974363.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
Pathogenic (Mar 04, 2014)	no assertion criteria provided Method: clinical testing	Congenital isolated adrenocorticotropic hormone deficiency Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000805093.1 First in ClinVar: Mar 11, 2018 Last updated: Mar 11, 2018

Comment:

Variant summary: TBX19 c.782delA (p.Asn261IlefsX46) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.4e-05 in 251390 control chromosomes. c.782delA has been reported in the literature in multiple individuals affected with Adrenocorticotropic Hormone Deficiency in the homozyous and compound heterozyous state (Metherell_2004, Vallette-Kasic_2005, Pulichino_2003). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

The TBX19 c.782delA variant is predicted to result in a frameshift and premature protein termination (p.Asn261Ilefs*46). This variant has been reported in patients with isolated ACTH deficiency (Pulichino et al. 2003. PubMed ID: 12651888; Jullien et al. 2020. PubMed ID: 33098107). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-168274298-CA-C). Frameshift variants in TBX19 are expected to be pathogenic. This variant is interpreted as pathogenic.

Comment:

The c.782delA pathogenic variant in the TBX19 gene has been reported previously in association with isolated ACTH deficiency (Metherell et al., 2004). The c.782delA variant causes a frameshift starting with codon Asparagine 261, changes this amino acid to an Isoleucine residue, and creates a premature Stop codon at position 46 of the new reading frame, denoted p.Asn261IlefsX46. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.782delA variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.782delA as apathogenic variant.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Congenital isolated adrenocorticotropin deficiency: an underestimated cause of neonatal death, explained by TPIT gene mutations.	Vallette-Kasic S	The Journal of clinical endocrinology and metabolism	2005	PMID: 15613420
TPIT mutations are associated with early-onset, but not late-onset isolated ACTH deficiency.	Metherell LA	European journal of endocrinology	2004	PMID: 15476446
Human and mouse TPIT gene mutations cause early onset pituitary ACTH deficiency.	Pulichino AM	Genes & development	2003	PMID: 12651888

Text-mined citations for rs730880274 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_005149.3(TBX19):c.782del (p.Asn261fs)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs730880274 ...