NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln) AND Ghosal hematodiaphyseal dysplasia

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Mar 25, 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:: RCV001283757.9

Allele description [Variation Report for NM_001061.7(TBXAS1):c.1235G>A (p.Arg412Gln)]

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)

Name:: Ghosal hematodiaphyseal dysplasia
Synonyms:: Ghosal hematodiaphyseal dysplasia syndrome; Ghosal syndrome
Identifiers:: MONDO: MONDO:0009274; MedGen: C1856465; Orphanet: 1802; OMIM: 231095

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001450722	Allergy Immunology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh	no assertion criteria provided	Likely pathogenic (Dec 21, 2020)	germline	clinical testing
SCV001469125	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Aug 7, 2020)	germline	clinical testing
SCV002519849	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2019)	Pathogenic (May 4, 2022)	germline	clinical testing	Citation Link,
SCV002547326	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004048100	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004244382	Suma Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29068549, 25741868
SCV004805950	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 25, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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
North Indian	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Expanding the genetic architecture and phenotypic spectrum in the skeletal ciliopathies.

Zhang W, Taylor SP, Ennis HA, Forlenza KN, Duran I, Li B, Sanchez JAO, Nevarez L, Nickerson DA, Bamshad M; University of Washington Center for Mendelian Genomics., Lachman RS, Krakow D, Cohn DH.

Hum Mutat. 2018 Jan;39(1):152-166. doi: 10.1002/humu.23362. Epub 2017 Nov 6.

PubMed [citation]

PMID:: 29068549
PMCID:: PMC6198324

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; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Allergy Immunology Laboratory, Postgraduate Institute of Medical Education and Research, Chandigarh, SCV001450722.1

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

Description

c.1376G>A: In-silico predictions for this variant are damaging and probably damaging. Two other missense variants affecting the same codon have been previously reported with Ghosal hematodiaphyseal syndrome. The variant was present in a heterozygous state with another variant on the other allele c.125_138del; p.Lys42ThrfsTer47. Additionally it was present in homozygous state in another patient.

#	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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001469125.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mendelics, SCV002519849.1

#	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 Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India, SCV002547326.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004048100.1

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

Description

A variant in the next codon (c.1376G>A) has been previously reported as variant of uncertain significance in consanguineous family with Ghosal hematodiaphyseal dysplasia syndrome (David Genevie`ve, 2008) and has been submitted to ClinVar as Variant of Uncertain Significance. The missense variant is predicted to be tolerated by both SIFT or PolyPhen2. The nucleotide is not conserved according to a GERP++ and PhyloP analysis of 100 vertebrates. The variant is observed in 0.0035% alleles in gnomAD Exomes with 1 individual carrying it in a homozygous state and hence it has been classified as a variant of Uncertain Significance.

#	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 Suma Genomics, SCV004244382.1

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

#	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 Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004805950.1

#	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

Last Updated: May 12, 2024

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