NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln) AND not provided

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV001571663.14

Allele description

NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)

Gene:

TBXAS1:thromboxane A synthase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q34

Genomic location:

Preferred name:

NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)

Other names:

R413E

HGVS:

NC_000007.14:g.140015731G>A
NG_008422.2:g.242350G>A
NM_001061.7:c.1235G>AMANE SELECT
NM_001130966.5:c.1235G>A
NM_001166253.4:c.1373G>A
NM_001166254.4:c.1034G>A
NM_001314028.4:c.1178G>A
NM_001366537.3:c.1052G>A
NM_030984.6:c.1235G>A
NP_001052.3:p.Arg412Gln
NP_001124438.2:p.Arg412Gln
NP_001159725.2:p.Arg458Gln
NP_001159726.1:p.Arg345Gln
NP_001300957.1:p.Arg393Gln
NP_001353466.1:p.Arg351Gln
NP_112246.3:p.Arg412Gln
LRG_579t4:c.1376G>A
LRG_579:g.242350G>A
NC_000007.13:g.139715531G>A
NM_001061.4:c.1238G>A
NM_001166253.1:c.1376G>A
NM_001166253.3:c.1373G>A

Protein change:

R345Q; ARG413GLU

Links:

OMIM: 274180.0004; dbSNP: rs199422117

NCBI 1000 Genomes Browser:

rs199422117

Molecular consequence:

NM_001061.7:c.1235G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001130966.5:c.1235G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166253.4:c.1373G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001166254.4:c.1034G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001314028.4:c.1178G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001366537.3:c.1052G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_030984.6:c.1235G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001796173	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 22, 2019)	germline	clinical testing	Citation Link,
SCV002278412	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18264100, 27156553, 33185009, 33244729, 35395429, 8702713, 28492532
SCV004032776	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001796173

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 22, 2019)

germline

clinical testing

Citation Link,

SCV002278412

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

SCV004032776

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Likely pathogenic
(Feb 1, 2024)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome).

Geneviève D, Proulle V, Isidor B, Bellais S, Serre V, Djouadi F, Picard C, Vignon-Savoye C, Bader-Meunier B, Blanche S, de Vernejoul MC, Legeai-Mallet L, Fischer AM, Le Merrer M, Dreyfus M, Gaussem P, Munnich A, Cormier-Daire V.

Nat Genet. 2008 Mar;40(3):284-6. doi: 10.1038/ng.2007.66. Epub 2008 Feb 10.

PubMed [citation]

PMID:: 18264100

Ghosal Type Hematodiaphyseal Dysplasia.

Jeevan A, Doyard M, Kabra M, Daire VC, Gupta N.

Indian Pediatr. 2016 Apr;53(4):347-8.

PubMed [citation]

PMID:: 27156553

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV001796173.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33185009, 27156553, 18264100)

#	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		not provided	not provided	not provided	not provided

From Invitae, SCV002278412.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 413 of the TBXAS1 protein (p.Arg413Gln). This variant is present in population databases (rs199422117, gnomAD 0.6%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Ghosal hematodiaphyseal dysplasia (PMID: 18264100, 27156553, 33185009, 33244729, 35395429). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 11889). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects TBXAS1 function (PMID: 8702713). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been 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

From CeGaT Center for Human Genetics Tuebingen, SCV004032776.7

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

Description

TBXAS1: PM3:Strong, PM2:Supporting, PP4, PS3:Supporting

#	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		3	not provided	not provided	not provided

Last Updated: Jun 17, 2024

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