Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002035432 | SCV002231214 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2022-04-18 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Thr188Serfs*39) in the POMGNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POMGNT1 are known to be pathogenic (PMID: 19299310, 20816175, 21447391, 26908613, 27391550). This variant is present in population databases (rs757322014, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with POMGNT1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV002563625 | SCV003761193 | uncertain significance | Muscular dystrophy-dystroglycanopathy | 2023-01-24 | criteria provided, single submitter | curation | The p.Thr188fs variant in POMGNT1 has not been previously reported in the literature in individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy, but has been identified in 0.02% (6/34588) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs949714416). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID#1451968) and has been interpreted as pathogenic by Invitae. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 188 and leads to a premature termination codon 39 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function is an established disease mechanism in autosomal recessive POMGNT1-associated muscular dystrophy-dystroglycanopathy. In summary, the clinical significance of the p.Thr188fs variant is uncertain. ACMG/AMP Criteria applied: PVS1 (Richards 2015). |