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NM_019892.6(INPP5E):c.1162G>T (p.Val388Leu) AND Familial aplasia of the vermis

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Apr 16, 2022
Review status:
criteria provided, conflicting classifications
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:
RCV000201647.4

Allele description [Variation Report for NM_019892.6(INPP5E):c.1162G>T (p.Val388Leu)]

NM_019892.6(INPP5E):c.1162G>T (p.Val388Leu)

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.1162G>T (p.Val388Leu)
HGVS:
  • NC_000009.12:g.136433073C>A
  • NG_016126.1:g.11732G>T
  • NM_001318502.2:c.1162G>T
  • NM_019892.6:c.1162G>TMANE SELECT
  • NP_001305431.1:p.Val388Leu
  • NP_063945.2:p.Val388Leu
  • NC_000009.11:g.139327525C>A
  • NM_019892.4:c.1162G>T
Protein change:
V388L
Links:
dbSNP: rs863225201
NCBI 1000 Genomes Browser:
rs863225201
Molecular consequence:
  • NM_001318502.2:c.1162G>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_019892.6:c.1162G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Familial aplasia of the vermis
Synonyms:
CEREBELLOPARENCHYMAL DISORDER IV; Joubert syndrome; Cerebelloparenchymal disorder 4; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0018772; MedGen: C0431399; Orphanet: 475; OMIM: PS213300

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000256424UW Hindbrain Malformation Research Program, University of Washington

See additional submitters

criteria provided, single submitter

(Bachmann-Gagescu et al. (J Med Genet. 2015))
Pathogenic
(Feb 23, 2015)
unknownresearch

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

SCV003013735Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Uncertain significance
(Apr 16, 2022)
germlineclinical testing

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

Summary from all submissions

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

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From UW Hindbrain Malformation Research Program, University of Washington, SCV000256424.1

#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, SCV003013735.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 388 of the INPP5E protein (p.Val388Leu). This variant is present in population databases (no rsID available, gnomAD 0.002%). This missense change has been observed in individual(s) with Joubert syndrome and related disorders and/or retinitis pigmentosa (PMID: 26092869; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 217663).

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

Last Updated: Feb 20, 2024