Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000050002 | SCV000220779 | likely pathogenic | Muscle eye brain disease | 2014-10-10 | criteria provided, single submitter | literature only | |
Clinical Genetics and Genomics, |
RCV001269853 | SCV001450159 | likely pathogenic | not provided | 2016-01-12 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV001853064 | SCV002138510 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2023-09-21 | criteria provided, single submitter | clinical testing | This variant is also known as G1908A. This missense change has been observed in individuals with muscle-eye-brain disease (PMID: 12849864, 21361872). This variant is present in population databases (rs267606962, gnomAD 0.009%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 605 of the POMGNT1 protein (p.Arg605His). ClinVar contains an entry for this variant (Variation ID: 56589). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg605 amino acid residue in POMGNT1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 19679478, 21361872, 24731844; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects POMGNT1 function (PMID: 21361872). 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 POMGNT1 protein function. |
Gene |
RCV001269853 | SCV002522021 | pathogenic | not provided | 2024-08-12 | criteria provided, single submitter | clinical testing | Published functional studies demonstrate a complete loss of catalytic activity (PMID: 21361872); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17906881, 20215985, 17154333, 12849864, 33726816, 33200426, 31964843, 35846108, 24731844, 21361872) |
Broad Center for Mendelian Genomics, |
RCV002513696 | SCV003761150 | likely pathogenic | Muscular dystrophy-dystroglycanopathy | 2023-01-24 | criteria provided, single submitter | curation | The p.Arg605His variant in POMGNT1 has been reported in at least six individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 33726816, 17154333, 12849864, 17906881, 20215985), and has been identified in 0.009% (2/21378) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs267606962). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID #56589) as pathogenic by Invitae and GeneDx, as probable-pathogenic by Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM), and as Likely Pathogenic by Counsyl and the Clinical Genetics Karolinska University Hospital (Karolinska University Hospital). Of the six affected individuals, two were homozygous, and two were compound heterozygotes who carried pathogenic/likely pathogenic variants in trans, which increases the likelihood that the p.Arg605His variant is pathogenic (PMID: 33726816, 17154333, 12849864, 17906881). In vitro functional studies provide some evidence that the p.Arg605His variant may impact protein function, as reflected by reduced catalytic activity in an in vitro enzymatic activity assay (PMID: 21361872). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PM3_Strong, PM2_supporting, PS3_Supporting, PP3 (Richards 2015). |
Baylor Genetics | RCV003460642 | SCV004205966 | pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 | 2024-02-15 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV005016346 | SCV005647637 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3; Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3; Retinitis pigmentosa 76 | 2024-05-31 | criteria provided, single submitter | clinical testing | |
Juha Muilu Group; Institute for Molecular Medicine Finland |
RCV000050002 | SCV000082411 | probable-pathogenic | Muscle eye brain disease | no assertion criteria provided | not provided | Converted during submission to Likely pathogenic. |