Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV002004850 | SCV002234086 | pathogenic | Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2023-11-06 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Trp206*) 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 (no rsID available, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with muscular dystrophy (PMID: 31069529). ClinVar contains an entry for this variant (Variation ID: 1450461). 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, |
RCV002564359 | SCV003761192 | likely pathogenic | Muscular dystrophy-dystroglycanopathy | 2023-01-24 | criteria provided, single submitter | curation | The p.Trp206Ter variant in POMGNT1 has been reported in 1 individual, in the homozygous state, with POMGNT1-associated muscular dystrophy-dystroglycanopathy, and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1156647434). 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#1450461) and has been interpreted as pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 206, which is 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, this variant meets criteria to be classified as pathogenic for POMGNT1-associated muscular dystrophy-dystroglycanopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting, PM3_supporting (Richards 2015). |
Neuberg Centre For Genomic Medicine, |
RCV004816815 | SCV005438655 | likely pathogenic | Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 | 2023-06-22 | criteria provided, single submitter | clinical testing | The observed stop gained c.617G>Ap.Trp206Ter variant in POMGNT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is reported with the allele frequency of 0.0004% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function variants have been previously reported to be disease causing. Computational evidence MutationTaster - Disease causing automatic predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Likely Pathogenic. |