NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter) AND Joubert syndrome 21

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Nov 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:: RCV000087069.10

Allele description [Variation Report for NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter)]

NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter)

Genes:

ARFGEF1:ADP ribosylation factor guanine nucleotide exchange factor 1 [Gene - OMIM - HGNC]
CSPP1:centrosome and spindle pole associated protein 1 [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

8q13.2

Genomic location:

Preferred name:

NM_001382391.1(CSPP1):c.3227dup (p.Tyr1076Ter)

HGVS:

NC_000008.11:g.67190656dup
NG_034100.1:g.131289dup
NM_001291339.2:c.2177dup
NM_001363131.2:c.3146dup
NM_001363132.2:c.3032dup
NM_001363133.2:c.2951dup
NM_001364869.1:c.3293dup
NM_001364870.1:c.3113dup
NM_001382391.1:c.3227dupMANE SELECT
NM_024790.6:c.3212dup
NP_001278268.1:p.Tyr726Ter
NP_001350060.1:p.Tyr1049Ter
NP_001350061.1:p.Tyr1011Ter
NP_001350062.1:p.Tyr984Ter
NP_001351798.1:p.Tyr1098Ter
NP_001351799.1:p.Tyr1038Ter
NP_001369320.1:p.Tyr1076Ter
NP_079066.5:p.Tyr1071Ter
NC_000008.10:g.68102890_68102891insA
NC_000008.10:g.68102891dup
NM_024790.6:c.3212dupA

Protein change:

Y1011*

Links:

OMIM: 611654.0004; dbSNP: rs587777141

NCBI 1000 Genomes Browser:

rs587777141

Molecular consequence:

NM_001291339.2:c.2177dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001363131.2:c.3146dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001363132.2:c.3032dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001363133.2:c.2951dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001364869.1:c.3293dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001364870.1:c.3113dup - nonsense - [Sequence Ontology: SO:0001587]
NM_001382391.1:c.3227dup - nonsense - [Sequence Ontology: SO:0001587]
NM_024790.6:c.3212dup - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Joubert syndrome 21 (JBTS21)
Identifiers:: MONDO: MONDO:0014288; MedGen: C3810212; OMIM: 615636

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000119883	OMIM	no assertion criteria provided	Pathogenic (Jan 2, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000256398	UW Hindbrain Malformation Research Program, University of Washington See additional submitters University of Washington Center for Mendelian Genomics, University of Washington	criteria provided, single submitter (Bachmann-Gagescu et al. (J Med Genet. 2015))	Pathogenic (Feb 23, 2015)	unknown	research	PubMed (1) [See all records that cite this PMID]
SCV002243823	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 10, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24360807, 24360808, 28492532
SCV002588793	DASA	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 3, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24360808, 25741868

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
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
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	research

Citations

PubMed

Joubert syndrome: a model for untangling recessive disorders with extreme genetic heterogeneity.

Bachmann-Gagescu R, Dempsey JC, Phelps IG, O'Roak BJ, Knutzen DM, Rue TC, Ishak GE, Isabella CR, Gorden N, Adkins J, Boyle EA, de Lacy N, O'Day D, Alswaid A, Ramadevi A R, Lingappa L, Lourenço C, Martorell L, Garcia-Cazorla À, Ozyürek H, Haliloğlu G, Tuysuz B, et al.

J Med Genet. 2015 Aug;52(8):514-22. doi: 10.1136/jmedgenet-2015-103087. Epub 2015 Jun 19.

PubMed [citation]

PMID:: 26092869
PMCID:: PMC5082428

Mutations in CSPP1 lead to classical Joubert syndrome.

Akizu N, Silhavy JL, Rosti RO, Scott E, Fenstermaker AG, Schroth J, Zaki MS, Sanchez H, Gupta N, Kabra M, Kara M, Ben-Omran T, Rosti B, Guemez-Gamboa A, Spencer E, Pan R, Cai N, Abdellateef M, Gabriel S, Halbritter J, Hildebrandt F, van Bokhoven H, et al.

Am J Hum Genet. 2014 Jan 2;94(1):80-6. doi: 10.1016/j.ajhg.2013.11.015. Epub 2013 Dec 19.

PubMed [citation]

PMID:: 24360807
PMCID:: PMC3882909

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000119883.3

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

Description

In 3 unrelated Brazilian patients with Joubert syndrome-21 (JBTS21; 615636), Tuz et al. (2014) identified compound heterozygous mutations in the CSPP1 gene: a 1-bp insertion (c.3211_3212insA), resulting in a frameshift and premature termination (Tyr1071Ter), and a G-to-A transition in intron 22 (c.2953+1G-A; 611654.0005), resulting in a splice site mutation.

#	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 UW Hindbrain Malformation Research Program, University of Washington, SCV000256398.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV002243823.3

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

Description

ClinVar contains an entry for this variant (Variation ID: 100669). For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with Joubert syndrome and related disorders (PMID: 24360808). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1071*) in the CSPP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CSPP1 are known to be pathogenic (PMID: 24360807, 24360808).

#	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 DASA, SCV002588793.1

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

Description

The c.3212dup;p.(Tyr1071*) variant creates a premature translational stop signal in the CSPP1 gene. It is expected to result in an absent or disrupted protein product - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 10066; PMID: 24360808) - PS4. This variant is not present in population databases (rs587777141, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic.

#	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

Last Updated: Feb 14, 2024

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