Submissions for variant NM_032806.6(POMGNT2):c.1219C>T (p.Arg407Trp)

gnomAD frequency: 0.00058  dbSNP: rs138480528

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000117209	SCV000491750	uncertain significance	not provided	2021-07-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000548186	SCV000652771	uncertain significance	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 8	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 407 of the POMGNT2 protein (p.Arg407Trp). This variant is present in population databases (rs138480528, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with POMGNT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 129214). 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 not expected to disrupt POMGNT2 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000117209	SCV004226094	uncertain significance	not provided	2023-02-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV002464113	SCV000248577	uncertain significance	not specified	2013-09-30	no assertion criteria provided	clinical testing	DNA sequence analysis of the POMGNT2 gene demonstrated a sequence change, c.1219C>T, in exon 2 that results in an amino acid change, p.Arg407Trp. This sequence change does not appear to have been previously described in patients with POMGNT2-related disorders and has been described in the Exome Aggregation Consortium with a low population frequency of 0.025% (dbSNP rs138480528). The p.Arg407Trp change affects a moderately conserved amino acid residue located in a domain of the POMGNT2 protein that is not known to be functional. The p.Arg407Trp substitution appears to be deleterious/possibly damaging using several in-silico pathogenicity prediction tools (SIFT PolyPhen2, MutationTaster). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg407Trp change remains unknown at this time.