ClinVar Miner

Submissions for variant NM_019892.6(INPP5E):c.1670G>A (p.Arg557His)

gnomAD frequency: 0.00001  dbSNP: rs992814593
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ocular Genomics Institute, Massachusetts Eye and Ear RCV001376234 SCV001573306 likely pathogenic Rod-cone dystrophy 2021-04-08 criteria provided, single submitter research The INPP5E c.1670G>A variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PP3, PM1, PM3. Based on this evidence we have classified this variant as Likely Pathogenic.
Invitae RCV001871983 SCV002189853 likely pathogenic Familial aplasia of the vermis 2022-04-26 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with rod-cone degeneration (PMID: 34188062). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1065659). 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. This variant disrupts the p.Arg557 amino acid residue in INPP5E. Other variant(s) that disrupt this residue have been observed in individuals with INPP5E-related conditions (PMID: 25999675), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 557 of the INPP5E protein (p.Arg557His).

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