Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001852649 | SCV002300515 | likely pathogenic | Mucolipidosis type II; Pseudo-Hurler polydystrophy | 2021-08-26 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 39061). This missense change has been observed in individuals with mucolipidosis III alpha/beta (PMID: 19197337). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with tyrosine at codon 956 of the GNPTAB protein (p.His956Tyr). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and tyrosine. 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 GNPTAB protein function. 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. This variant disrupts the p.His956 amino acid residue in GNPTAB. Other variant(s) that disrupt this residue have been observed in individuals with GNPTAB-related conditions (PMID: 19617216), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 25505245, 31579991). |
Gene |
RCV000032326 | SCV000055971 | not provided | Pseudo-Hurler polydystrophy | no assertion provided | literature only |