Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001035890 | SCV001199230 | likely pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2; Autosomal recessive limb-girdle muscular dystrophy type 2N | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the POMT2 protein (p.Gly266Arg). This variant is present in population databases (rs761773211, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of POMT2-related muscular dystrophy and/or limb-girdle muscular dystrophy (PMID: 29175898; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 835081). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMT2 protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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, |
RCV003230622 | SCV003928381 | uncertain significance | not specified | 2023-04-26 | criteria provided, single submitter | clinical testing | Variant summary: POMT2 c.796G>A (p.Gly266Arg) results in a non-conservative amino acid change located in the glycosyl transferase family 39/83 domain (IPR003342) 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 2e-05 in 251476 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.796G>A has been reported in the literature in the compound heterozygous state in an individual affected with autosomal recessive Limb-Girdle Muscular Dystrophy (Ostergaard_2018). It has also been reported in the homozygous state in an individual from a consanguineous family who also had a homozygous variant in the GNE gene (c.538G>T, p.A180S) and was initially diagnosed with myopathy, but was ultimately given a dual diagnosis of Nonaka myopathy and POMT2-related Limb-Girdle-Muscular Dystrophy based on the results of genetic testing (Borklu-Yucel_2020). However, given the overlap in phenotype between these two conditions, it is difficult to determine how these variants each contribute to the causality of the patient phenotype in this case. Therefore, these data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32140910, 29175898). One clinical diagnostic laboratory has submitted a clinical-significance assessment for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. |
| Baylor Genetics | RCV003473613 | SCV004204101 | likely pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 | 2023-08-24 | criteria provided, single submitter | clinical testing |