Submissions for variant NM_019892.6(INPP5E):c.301G>C (p.Glu101Gln)

gnomAD frequency: 0.00004  dbSNP: rs566641584

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001202114	SCV001373215	uncertain significance	Familial aplasia of the vermis	2024-08-12	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 101 of the INPP5E protein (p.Glu101Gln). This variant is present in population databases (rs566641584, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with INPP5E-related conditions. ClinVar contains an entry for this variant (Variation ID: 933822). 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 not expected to disrupt INPP5E protein function with a negative predictive value of 95%. 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.
PreventionGenetics, part of Exact Sciences	RCV004528414	SCV004104341	uncertain significance	INPP5E-related disorder	2022-12-09	criteria provided, single submitter	clinical testing	The INPP5E c.301G>C variant is predicted to result in the amino acid substitution p.Glu101Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.016% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/9-139333571-C-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.