ClinVar Miner

Submissions for variant NM_017739.4(POMGNT1):c.1545del (p.Tyr516fs)

dbSNP: rs1434252108
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001390608 SCV001592397 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 2022-07-12 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1076645). This premature translational stop signal has been observed in individual(s) with clinical features of muscular dystrophy-dystroglycanopathy (PMID: 24282183). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Tyr516Thrfs*21) 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).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002551577 SCV003761157 pathogenic Muscular dystrophy-dystroglycanopathy 2023-01-24 criteria provided, single submitter curation The p.Tyr516fs variant in POMGNT1 has been previously reported in one individual, in the compound heterozygous state, with muscular dystrophy-dystroglycanopathy (PMID: 24282183), and has been identified in 0.003% (1/34592) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1434252108). 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#:1076645) 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 516 and leads to a premature termination codon 21 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the POMGNT1 gene 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 (Richards 2015).

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