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

gnomAD frequency: 0.00001  dbSNP: rs780882740

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
UW Hindbrain Malformation Research Program, University of Washington	RCV000201735	SCV000256422	pathogenic	Familial aplasia of the vermis	2015-02-23	criteria provided, single submitter	research
GeneDx	RCV001775666	SCV002012871	uncertain significance	not provided	2021-03-10	criteria provided, single submitter	clinical testing	Previously identified in individuals with Joubert syndrome who harbored a second INPP5E variant, however segregation to determine the phase of the variants was not reported (Bachmann-Gagescu et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26092869)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201735	SCV002233711	pathogenic	Familial aplasia of the vermis	2022-01-14	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt INPP5E protein function. ClinVar contains an entry for this variant (Variation ID: 217661). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). This variant is present in population databases (rs780882740, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 341 of the INPP5E protein (p.Gly341Ser).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	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).