Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV001565992 | SCV001789451 | uncertain significance | not provided | 2020-11-11 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Labcorp Genetics |
RCV001859407 | SCV002261424 | likely pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2023-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 485 of the POMGNT1 protein (p.Arg485Cys). This variant is present in population databases (rs755588045, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of retinitis pigmentosa (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: 1200851). 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 POMGNT1 protein function. 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. |
Broad Center for Mendelian Genomics, |
RCV002568438 | SCV003761205 | uncertain significance | Muscular dystrophy-dystroglycanopathy | 2023-01-24 | criteria provided, single submitter | curation | The p.Arg485Cys variant in POMGNT1 has not been previously reported in the literature in individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy, but has been identified in 0.005% (1/19952) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs755588045). 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#1200851) and has been interpreted as likely pathogenic by Invitae and as a variant of uncertain significance by GeneDx. 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, the clinical significance of the p.Arg485Cys variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015). |
Dept Of Ophthalmology, |
RCV003888304 | SCV004708062 | likely pathogenic | Retinal dystrophy | 2023-10-01 | criteria provided, single submitter | research | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV004770175 | SCV005381010 | uncertain significance | not specified | 2024-08-15 | criteria provided, single submitter | clinical testing | Variant summary: POMGNT1 c.1453C>T (p.Arg485Cys) results in a non-conservative amino acid change in 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 1.6e-05 in 251494 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1453C>T in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 1200851). Based on the evidence outlined above, the variant was classified as uncertain significance. |