ClinVar Miner

Submissions for variant NM_017739.4(POMGNT1):c.1814G>A (p.Arg605His)

dbSNP: rs267606962
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Total submissions: 8
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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, Karolinska University Hospital RCV001269853 SCV001450159 likely pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp 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.
GeneDx 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, Broad Institute of MIT and Harvard 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, 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 (FIMM) RCV000050002 SCV000082411 probable-pathogenic Muscle eye brain disease no assertion criteria provided not provided Converted during submission to Likely pathogenic.

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