VCV000598934.10 - ClinVar

NM_006346.4(PIBF1):c.1508A>G (p.Tyr503Cys)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Likely pathogenic

3 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006346.4(PIBF1):c.1508A>G (p.Tyr503Cys)

Variation ID: 598934 Accession: VCV000598934.10

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 13q22.1 13: 72908550 (GRCh38) [ NCBI UCSC ] 13: 73482688 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 12, 2019	Apr 13, 2025	May 2, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_006346.4:c.1508A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_006337.2:p.Tyr503Cys	missense
NM_001349655.2:c.1595A>G	NP_001336584.1:p.Tyr532Cys	missense
NR_146205.2:n.1795A>G		non-coding transcript variant
NR_146206.2:n.1795A>G		non-coding transcript variant
NC_000013.11:g.72908550A>G
NC_000013.10:g.73482688A>G
NG_053118.1:g.131527A>G

... more HGVS ... less HGVS

Protein change

Y503C, Y532C

Other names

Canonical SPDI

NC_000013.11:72908549:A:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

variation affecting protein; Variation Ontology [VariO:0002]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00005

The Genome Aggregation Database (gnomAD), exomes 0.00006

Exome Aggregation Consortium (ExAC) 0.00007

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA7002302 OMIM: 607532.0004 dbSNP: rs144610914 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
PIBF1		-	-	GRCh38 GRCh37	164	244

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Joubert syndrome 33	Likely pathogenic (5)	criteria provided, multiple submitters, no conflicts	May 2, 2024	RCV000735944.10
Cephalocele Joubert syndrome 33	Pathogenic (1)	no assertion criteria provided	Feb 18, 2019	RCV000779664.2
Dandy-Walker syndrome	Likely pathogenic (1)	no assertion criteria provided	-	RCV001257995.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Jan 18, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 33 Affected status: unknown Allele origin: germline	Johns Hopkins Genomics, Johns Hopkins University Accession: SCV001478434.1 First in ClinVar: Feb 07, 2021 Last updated: Feb 07, 2021	Publications: PubMed (2) PubMed: 26167768‚ 30858804 Comment: This PIBF1 variant (rs144610914) is rare (<0.1%) in a large population dataset (gnomAD: 15/273344 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. … (more) This PIBF1 variant (rs144610914) is rare (<0.1%) in a large population dataset (gnomAD: 15/273344 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. It has been reported in a compound heterozygous state with a nonsense variant in a patient with Joubert syndrome. Three bioinformatics tools predict this variant would be damaging The tyrosine residue at this position is strongly conserved across the species assessed. This variant is not predicted to affect normal exon 12 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1508A>G to be likely pathogenic. (less)
Likely pathogenic (May 22, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 33 Affected status: yes Allele origin: germline	3billion Accession: SCV002521045.1 First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Same nucleotide change resulting in same amino … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000598934). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Intellectual disability, severe (present) , Seizure (present) , Proportionate short stature (present) , Hypogonadotropic hypogonadism (present) , Clubfoot (present) , Monocular strabismus (present) , Atypical behavior (present) , Absent speech (present) , Short palm (present) , Tapered finger (present) , Scoliosis (present) , Spasticity (present) , Epicanthus (present) , Thick eyebrow (present) , Tooth malposition (present) , High palate (present) , Facial asymmetry (present) Zygosity: Single Heterozygote
Likely pathogenic (May 02, 2024) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Joubert syndrome 33 Affected status: yes Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV005200985.1 First in ClinVar: Sep 08, 2024 Last updated: Sep 08, 2024	Comment: PM1, PM3_Strong, PM2
Likely pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Dandy-Walker malformation Affected status: yes Allele origin: inherited	University of Washington Center for Mendelian Genomics, University of Washington Accession: SCV001434808.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (1) PubMed: 31474318
Pathogenic (Oct 27, 2020) N Not contributing to aggregate classification	no assertion criteria provided Method: literature only	JOUBERT SYNDROME 33 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001438709.2 First in ClinVar: Oct 25, 2020 Last updated: Oct 30, 2020	Publications: PubMed (1) PubMed: 30858804 Comment on evidence: In a 6-year-old girl, born of nonconsanguineous German parents, with Joubert syndrome (JBTS33; 617767), Ott et al. (2019) identified compound heterozygosity for mutations in the … (more) In a 6-year-old girl, born of nonconsanguineous German parents, with Joubert syndrome (JBTS33; 617767), Ott et al. (2019) identified compound heterozygosity for mutations in the PIBF1 gene: a c.1508A-G transition (c.1508A-G, NM_006346.2), resulting in a tyr503-to-cys (Y503C) substitution, and a c.1453C-T transition, resulting in a gln485-to-ter (Q485X; 607532.0005) substitution. Both mutations occurred at highly conserved residues. The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Each parent was heterozygous for one of the mutations. Expression analysis of wildtype and mutant PIBF1 constructs showed that both mutations resulted in the synthesis of stable proteins, with the Q485X mutant protein being smaller than wildtype. Ott et al. (2019) analyzed mutant pibf1 proteins in pibf1 knockdown Xenopus larval skin and found that the Q485X mutation resulted in a disturbed localization of pibf1 to the ciliary base, and the Y503C mutation resulted in attenuated rescue of pifb1. (less)
Pathogenic (-) N Not contributing to aggregate classification	no assertion criteria provided Method: research	Joubert syndrome 33 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics, Heidelberg University Accession: SCV000863406.2 First in ClinVar: Jan 12, 2019 Last updated: Apr 13, 2025	Comment: The variant is observed as compound heterozygous along with the variant at 13:73468052 in the PIBF1 gene. Sex: female
Pathogenic (Feb 18, 2019) N Not contributing to aggregate classification	no assertion criteria provided Method: research	JOUBERT SYNDROME 33 Cephalocele Affected status: yes Allele origin: germline	Dobyns Lab, Seattle Children's Research Institute Accession: SCV000916346.2 First in ClinVar: Jun 02, 2019 Last updated: Apr 13, 2025	Number of individuals with the variant: 1 Sex: female Ethnicity/Population group: Caucasian

Comment:

This PIBF1 variant (rs144610914) is rare (<0.1%) in a large population dataset (gnomAD: 15/273344 total alleles; 0.005%; no homozygotes) and has an entry in ClinVar. It has been reported in a compound heterozygous state with a nonsense variant in a patient with Joubert syndrome. Three bioinformatics tools predict this variant would be damaging The tyrosine residue at this position is strongly conserved across the species assessed. This variant is not predicted to affect normal exon 12 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1508A>G to be likely pathogenic.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000598934). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
variation affecting protein (VariO:0002)	Method not provided	Result not provided	Institute of Human Genetics, Heidelberg University Accession: SCV000863406.2

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Redefining the Etiologic Landscape of Cerebellar Malformations.	Aldinger KA	American journal of human genetics	2019	PMID: 31474318
The Frog Xenopus as a Model to Study Joubert Syndrome: The Case of a Human Patient With Compound Heterozygous Variants in PIBF1.	Ott T	Frontiers in physiology	2019	PMID: 30858804
An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.	Wheway G	Nature cell biology	2015	PMID: 26167768

Text-mined citations for rs144610914 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 20, 2025

ClinVar Genomic variation as it relates to human health

NM_006346.4(PIBF1):c.1508A>G (p.Tyr503Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs144610914 ...