Submissions for variant NM_001243766.1(POMGNT1):c.794G>A (p.Arg265His)

gnomAD frequency: 0.00004  dbSNP: rs386834010

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000250383	SCV000312923	likely benign	not specified		criteria provided, single submitter	clinical testing
Counsyl	RCV000049988	SCV000789433	uncertain significance	Muscle eye brain disease	2017-01-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001045717	SCV001209588	uncertain significance	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2022-08-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 265 of the POMGNT1 protein (p.Arg265His). This variant is present in population databases (rs386834010, gnomAD 0.02%). This missense change has been observed in individual(s) with muscle-eye-brain (MEB) disease and was observed to segregate with MEB in a family. In at least one individual this variant was observed in cis with p.Arg311Gln and in trans with a different POMGNT1 variant (PMID: 15236414, 17559086, 20215985, 22522420). ClinVar contains an entry for this variant (Variation ID: 56575). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects POMGNT1 function (PMID: 21361872, 24733390). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000250383	SCV002819697	uncertain significance	not specified	2022-12-20	criteria provided, single submitter	clinical testing	Variant summary: POMGNT1 c.794G>A (p.Arg265His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251420 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in POMGNT1 causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive (4e-05 vs 0.00072), allowing no conclusion about variant significance. c.794G>A has been reported in the literature as a maternally inherited complex allele in cis with c.932G>A (p.Arg311Gln) in an individual with features of Muscle-eye-brain disease (MEB) who harbored a paternally inherited variant c.1324C>T (p.Arg442Cys) in trans (example, Vervoort_2004). This complex allele has also been reported in compound heterozygosity with other POMGNT1 variants in individuals with features of POMGNT1-related disorders (example, Devisme_2012, Voglmeir_2011). These report(s) do not provide unequivocal conclusions about association of the variant in isolation with Limb-Girdle Muscular Dystrophy, Autosomal Recessive. At least one publication reports variant specific experimental evidence evaluating an impact on protein function (Voglmeir_2011). The most pronounced variant effect results in 21% of normal protein-O-mannose N-acetylglucosaminyltransferase 1 enzyme activity in vitro. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)	RCV000049988	SCV000082397	probable-pathogenic	Muscle eye brain disease		no assertion criteria provided	not provided	Converted during submission to Likely pathogenic.
Natera, Inc.	RCV000049988	SCV001461196	uncertain significance	Muscle eye brain disease	2020-09-16	no assertion criteria provided	clinical testing