ClinVar Miner

Submissions for variant NM_019892.6(INPP5E):c.1021G>A (p.Gly341Ser) (rs780882740)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
UW Hindbrain Malformation Research Program,University of Washington RCV000201735 SCV000256422 pathogenic Joubert syndrome 2015-02-23 criteria provided, single submitter research
Broad Institute Rare Disease Group, Broad Institute RCV001267700 SCV001445950 uncertain significance Joubert syndrome 1 2020-11-16 no assertion criteria provided curation The heterozygous p.Gly341Ser variant in INPP5E was identified by our study in the compound heterozygous state, along with another variant of uncertain significance, in 1 individual with Joubert syndrome 1. The variant has been reported in 3 individuals of unknown ethnicity with Joubert syndrome 1 (PMID: 26092869), and has been identified in 0.002% (2/109550) of European non-Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs780882740). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217661) as pathogenic by UW Hindbrain Malformation Research Program, University of Washington. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. The phenotype of an individual heterozygous for this variant is highly specific for Joubert syndrome 1 based on unique phenotype consistent with disease. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP4 (Richards 2015).

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