Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001852693 | SCV002282314 | likely pathogenic | Mucolipidosis type II; Pseudo-Hurler polydystrophy | 2023-11-07 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1018 of the GNPTAB protein (p.Asp1018Gly). This variant is present in population databases (rs281865007, gnomAD 0.0009%). This missense change has been observed in individuals with GNPTAB-related conditions (PMID: 19617216; Invitae). ClinVar contains an entry for this variant (Variation ID: 41256). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GNPTAB function (PMID: 25505245). This variant disrupts the p.Asp1018 amino acid residue in GNPTAB. Other variant(s) that disrupt this residue have been observed in individuals with GNPTAB-related conditions (PMID: 19617216, 29872134), 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. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003226172 | SCV003923180 | likely pathogenic | Mucolipidosis | 2023-03-03 | criteria provided, single submitter | clinical testing | Variant summary: GNPTAB c.3053A>G (p.Asp1018Gly) results in a non-conservative amino acid change located in the EF-hand domain (IPR002048) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251364 control chromosomes (gnomAD). c.3053A>G has been reported in the literature in individuals affected with Mucolipidosis (example: Cathey_2010). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (example: Qian_2015). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. |
| Gene |
RCV000034157 | SCV000058094 | not provided | Mucolipidosis type II | no assertion provided | literature only |