Submissions for variant NM_017739.4(POMGNT1):c.1489C>T (p.Arg497Ter)

gnomAD frequency: 0.00001  dbSNP: rs745343484

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001837127	SCV002097526	pathogenic	not provided	2022-08-20	criteria provided, single submitter	clinical testing	Identified in the heterozygous state in a female patient diagnosed with retinitis pigmentosa; patient also heterozygous for a variant in the EYS gene (Koyanagi et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31213501)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002034696	SCV002238716	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg497*) 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 (rs745343484, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with POMGNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1341631). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002542791	SCV003761161	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg497Ter 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% (1/19950) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs745343484). 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#:1341631) and has been interpreted as likely pathogenic by GeneDx and pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 497, 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	RCV003464155	SCV004205982	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2024-03-12	criteria provided, single submitter	clinical testing
Dept Of Ophthalmology, Nagoya University	RCV003888327	SCV004708051	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research