ClinVar Miner

Submissions for variant NM_017739.4(POMGNT1):c.511C>T (p.Arg171Ter)

dbSNP: rs1424631447
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000803088 SCV000942947 pathogenic Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 2023-02-05 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg171*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with dystroglycanopathy (PMID: 28688748). ClinVar contains an entry for this variant (Variation ID: 648374). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV002534735 SCV003761196 likely pathogenic Muscular dystrophy-dystroglycanopathy 2023-01-24 criteria provided, single submitter curation The p.Arg171Ter variant in POMGNT1 has been reported in two individuals with muscular dystrophy-dystroglycanopathy (PMID: 33200426, 28688748), and has been identified in 0.003% (1/28992) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1424631447). 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#:648374) and has been interpreted as pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 171, which is 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, 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: PVS1, PM2 (Richards 2015).
Baylor Genetics RCV003461142 SCV004206029 pathogenic Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3 2022-02-04 criteria provided, single submitter clinical testing

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