NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter) AND Spondyloepimetaphyseal dysplasia, PAPSS2 type

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 3, 2022
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:: RCV000007076.11

Allele description [Variation Report for NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter)]

NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter)

Gene:

PAPSS2:3'-phosphoadenosine 5'-phosphosulfate synthase 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.31

Genomic location:

Preferred name:

NM_001015880.2(PAPSS2):c.1000C>T (p.Arg334Ter)

HGVS:

NC_000010.11:g.87727403C>T
NG_012150.1:g.72685C>T
NM_001015880.2:c.1000C>TMANE SELECT
NM_004670.4:c.985C>T
NP_001015880.1:p.Arg334Ter
NP_004661.2:p.Arg329Ter
NC_000010.10:g.89487160C>T
NM_001015880.1:c.1000C>T
NM_004670.3:c.985C>T

Protein change:

R329*; ARG329TER

Links:

OMIM: 603005.0003; dbSNP: rs121908952

NCBI 1000 Genomes Browser:

rs121908952

Molecular consequence:

NM_001015880.2:c.1000C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_004670.4:c.985C>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Spondyloepimetaphyseal dysplasia, PAPSS2 type
Synonyms:: SEMD, PAKISTANI TYPE; Spondyloepimetaphyseal dysplasia, pakistani type; BRACHYOLMIA TYPE 4 WITH MILD EPIPHYSEAL AND METAPHYSEAL CHANGES
Identifiers:: MONDO: MONDO:0019666; MedGen: C2748515; Orphanet: 93282; OMIM: 612847

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000027272	OMIM	no assertion criteria provided	Pathogenic (May 28, 2009)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000807496	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 1, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19474428, 25741868, 25326635
SCV000926199	Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust	no assertion criteria provided	Pathogenic (May 3, 2019)	inherited	clinical testing
SCV002059114	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 3, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] PMID:19474428

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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	1	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

Inactivating PAPSS2 mutations in a patient with premature pubarche.

Noordam C, Dhir V, McNelis JC, Schlereth F, Hanley NA, Krone N, Smeitink JA, Smeets R, Sweep FC, Claahsen-van der Grinten HL, Arlt W.

N Engl J Med. 2009 May 28;360(22):2310-8. doi: 10.1056/NEJMoa0810489. Erratum in: N Engl J Med. 2009 Jul 9;361(2):217.

PubMed [citation]

PMID:: 19474428

Molecular findings among patients referred for clinical whole-exome sequencing.

Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, Ward P, Braxton A, Wang M, Buhay C, Veeraraghavan N, Hawes A, Chiang T, Leduc M, Beuten J, Zhang J, He W, Scull J, Willis A, Landsverk M, Craigen WJ, Bekheirnia MR, et al.

JAMA. 2014 Nov 12;312(18):1870-9. doi: 10.1001/jama.2014.14601.

PubMed [citation]

PMID:: 25326635
PMCID:: PMC4326249

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000027272.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the arg329-to-ter (R329X) mutation in the PAPSS2 gene that was found in compound heterozygous state in a family segregating brachyolmia type 4 with mild epiphyseal and metaphyseal changes (BCYM4; 612847) by Noordam et al. (2009), see 603005.0002.

#	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		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV000807496.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing (GTR000508680.4)	PubMed (3)

Description

This variant has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with IUGR, failure to thrive, microcephaly, chondrodystrophy, severe kyphoscoliosis, asymmetric chest with rib flaring, mild knee contractures, asymmetric face with maxillary and orbital hypoplasia, dysmorphism, hypotonia, PDA

#	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	(GTR000508680.4)	not provided	not provided	not provided	not provided

From Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, SCV000926199.1

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

From 3billion, SCV002059114.1

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

Description

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000036, PM2_M). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000006688, PMID:19474428). 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	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Jun 23, 2024

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