Submissions for variant NM_017739.4(POMGNT1):c.1463G>A (p.Arg488Gln)

gnomAD frequency: 0.00002  dbSNP: rs766382416

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479982	SCV000571942	likely pathogenic	not provided	2016-10-17	criteria provided, single submitter	clinical testing	The R488Q variant in the POMGNT1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R488Q variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R488Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (C490Y and P493R) have been reported in the Human Gene Mutation Database in association with POMGNT1-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The R488Q variant is a strong candidate for a pathogenic variant.
Invitae	RCV001368114	SCV001564495	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-08-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 488 of the POMGNT1 protein (p.Arg488Gln). This variant is present in population databases (rs766382416, gnomAD 0.004%). 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: 422459). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POMGNT1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002525910	SCV003761163	uncertain significance	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg488Gln variant in POMGNT1 has not been previously reported in the literature in individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy, but has been identified in 0.004% (5/113768) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs766382416). 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#:422459) as likely pathogenic by GeneDx and as a variant of uncertain significance by Counsyl and Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg488Gln variant is uncertain. ACMG/AMP Criteria applied: PM2_Supporting, PP3 (Richards 2015).
Counsyl	RCV000984206	SCV001132273	uncertain significance	Muscle eye brain disease	2017-11-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984207	SCV001132274	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2017-11-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984208	SCV001132275	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O	2017-11-02	no assertion criteria provided	clinical testing
Counsyl	RCV000984209	SCV001132276	uncertain significance	Retinitis pigmentosa 76	2017-11-02	no assertion criteria provided	clinical testing