Submissions for variant NM_017739.4(POMGNT1):c.1462C>T (p.Arg488Ter)

dbSNP: rs727504103

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823735	SCV000964605	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg488*) 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 (rs727504103, gnomAD 0.0009%). 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: 665448). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001266791	SCV001444970	pathogenic	Inborn genetic diseases	2018-07-02	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002535998	SCV003761164	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg488Ter variant in POMGNT1 has not been previously reported in the literature in individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy, but has been identified in 0.0009% (1/113768) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs727504103). 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#: 665448) and has been interpreted as pathogenic by Ambry Genetics and Invitae. This nonsense variant leads to a premature termination codon at amino acid position 488 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	RCV003461286	SCV004205970	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2024-02-19	criteria provided, single submitter	clinical testing
Clinical Laboratory Sciences Program (CLSP), King Saud bin Abdulaziz University for Health Sciences (KSAU-HS)	RCV003326497	SCV003927943	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O	2023-04-01	no assertion criteria provided	clinical testing