NM_014112.5(TRPS1):c.769C>T (p.Arg257Ter) AND Trichorhinophalangeal dysplasia type I

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: May 16, 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:: RCV002471204.3

Allele description [Variation Report for NM_014112.5(TRPS1):c.769C>T (p.Arg257Ter)]

NM_014112.5(TRPS1):c.769C>T (p.Arg257Ter)

Gene:

TRPS1:transcriptional repressor GATA binding 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q23.3

Genomic location:

Preferred name:

NM_014112.5(TRPS1):c.769C>T (p.Arg257Ter)

HGVS:

NC_000008.11:g.115619329G>A
NG_012383.3:g.54673C>T
NM_001282902.3:c.742C>T
NM_001282903.3:c.748C>T
NM_001330599.2:c.730C>T
NM_014112.5:c.769C>TMANE SELECT
NP_001269831.1:p.Arg248Ter
NP_001269832.1:p.Arg250Ter
NP_001317528.1:p.Arg244Ter
NP_054831.2:p.Arg257Ter
NC_000008.10:g.116631556G>A
NM_014112.4:c.769C>T

Protein change:

R244*

Links:

dbSNP: rs2130531352

NCBI 1000 Genomes Browser:

rs2130531352

Molecular consequence:

NM_001282902.3:c.742C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001282903.3:c.748C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001330599.2:c.730C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_014112.5:c.769C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Trichorhinophalangeal dysplasia type I (TRPS1)
Synonyms:: TRPS I; Trichorhinophalangeal syndrome type 1; Giedion syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008596; MedGen: C0432233; Orphanet: 77258; OMIM: 190350

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002766941	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23621477, 25741868
SCV003916021	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	no assertion criteria provided	Likely pathogenic (Apr 13, 2023)	germline	clinical testing
SCV004175242	Genetics and Molecular Pathology, SA Pathology See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 16, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23621477, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002766941

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 2, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003916021

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

no assertion criteria provided

Likely pathogenic
(Apr 13, 2023)

germline

clinical testing

SCV004175242

Genetics and Molecular Pathology, SA Pathology

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(May 16, 2023)

germline

clinical testing

PubMed (2)
[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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A novel de novo nonsense mutation in the TRPS1 gene in a Japanese patient with tricho-rhino-phalangeal syndrome type I.

Farooq M, Fujikawa H, Fujimoto A, Kubo Y, Ito M, Shimomura Y.

Int J Dermatol. 2014 Aug;53(8):1012-5. doi: 10.1111/j.1365-4632.2012.05694.x. Epub 2013 Apr 28. No abstract available.

PubMed [citation]

PMID:: 23621477

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 Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002766941.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with trichorhinophalangeal syndrome, type I (MIM#190350). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by a clinical laboratory in ClinVar and observed as de novo in an individual with trichorhinophalangeal syndrome type I (PMID: 23621477). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

#	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 Zotz-Klimas Genetics Lab, MVZ Zotz Klimas, SCV003916021.1

#	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 Genetics and Molecular Pathology, SA Pathology, SCV004175242.1

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

Description

The TRPS1 c.769C>T variant is classified as a PATHOGENIC variant (PVS1, PS4_moderate, PM2, PP4) The variant is a single nucleotide change at exon 3/7 of the TRPS1 gene which is predicted to result in a premature termination of the protein product at codon 257. This variant is predicted to cause loss of normal protein function which is a known mechanism of disease for the TRPS1 gene (PVS1). The variant has not been reported in dbSNP and is absent from population databases (PM2). The variant has been previously identified in at least two (or more) individuals affected with Trichorhinoplalangeal syndrome (PMID: 23621477, ClinVar) (PS4_moderate). The variant has been reported in ClinVar (Variation ID: #1459463) or HGMD (Accession no.: CM134356) as Pathogenic/ disease causing. The patient's phenotype is highly specific for the TRPS1 gene (PP4).

#	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

Last Updated: Sep 29, 2024

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