NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu) AND Joubert syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Pathogenic(1);Uncertain significance(1) (Last evaluated: Sep 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000201594.3

Allele description [Variation Report for NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu)]

NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu)

Gene:
INPP5E:inositol polyphosphate-5-phosphatase E [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
9q34.3
Genomic location:
Preferred name:
NM_019892.6(INPP5E):c.944C>T (p.Pro315Leu)
HGVS:
  • NC_000009.12:g.136434127G>A
  • NG_016126.1:g.10678C>T
  • NM_001318502.2:c.944C>T
  • NM_019892.6:c.944C>TMANE SELECT
  • NP_001305431.1:p.Pro315Leu
  • NP_063945.2:p.Pro315Leu
  • NC_000009.11:g.139328579G>A
  • NM_019892.4:c.944C>T
Protein change:
P315L
Links:
dbSNP: rs754637179
NCBI 1000 Genomes Browser:
rs754637179
Molecular consequence:
  • NM_001318502.2:c.944C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_019892.6:c.944C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Joubert syndrome (JBTS)
Synonyms:
CEREBELLOPARENCHYMAL DISORDER IV; Cerebelloparenchymal disorder 4; Cerebellar vermis agenesis; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300; Human Phenotype Ontology: HP:0002335

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000256423UW Hindbrain Malformation Research Program,University of Washington

See additional submitters

criteria provided, single submitter
Pathogenic
(Feb 23, 2015)
unknownresearch

PubMed (1)
[See all records that cite this PMID]

SCV000758383Invitaecriteria provided, single submitter
Uncertain significance
(Sep 11, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownyesnot providednot providednot providednot providednot providedresearch
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

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

Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.

Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA.

Ophthalmology. 2017 Sep;124(9):1314-1331. doi: 10.1016/j.ophtha.2017.04.008. Epub 2017 May 27.

PubMed [citation]
PMID:
28559085
PMCID:
PMC5565704
See all PubMed Citations (3)

Details of each submission

From UW Hindbrain Malformation Research Program,University of Washington, SCV000256423.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedresearch PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000758383.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces proline with leucine at codon 315 of the INPP5E protein (p.Pro315Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs754637179, ExAC 0.01%). This variant has been reported in combination with another INPP5E variant in several individuals affected with Joubert syndrome (PMID: 26092869, 28559085, Invitae). ClinVar contains an entry for this variant (Variation ID: 217662). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Apr 12, 2021

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