Submissions for variant NM_017739.4(POMGNT1):c.1324C>T (p.Arg442Cys)

gnomAD frequency: 0.00004  dbSNP: rs28940869

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000150001	SCV000196861	pathogenic	not provided	2017-05-11	criteria provided, single submitter	clinical testing	p.Arg442Cys (CGT>TGT): c.1324 C>T in exon 16 in the POMGNT1 gene (NM_017739.3). The R442C mutation in the POMGNT1 gene has been reported previously in mutiple individuals including 3 children with muscle-eye-brain disease (MEB), as well as two siblings with MEB and clinical features that included congenital hypotonia, global developmental delay, intellectual disability, early-onset glaucoma, and MRI findings characteristic of MEB (Hehr et al., 2007; Vervoort et al., 2004). Functional studies demonstrated complete loss of enzyme activity resulting from the R442C mutation in POMGNT1 (Voglmeir et al., 2011). The R442C mutation 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 R442C mutation is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this mutation is probably damaging to the protein structure/function. Missense mutations at the same and a nearby residue (R442L, R442H, L440R) have been reported in association with muscle-eye-brain disease, supporting the functional importance of this region of the protein. We interpret R442C as a disease-causing mutation. The variant is found in POMGNT1 panel(s).
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000150001	SCV000281499	pathogenic	not provided	2015-12-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000150001	SCV000331827	pathogenic	not provided	2015-08-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000150001	SCV000843376	likely pathogenic	not provided	2017-12-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984210	SCV001162922	pathogenic	Muscle eye brain disease		criteria provided, single submitter	clinical testing
Invitae	RCV001219572	SCV001391518	pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O; Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2023-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 442 of the POMGNT1 protein (p.Arg442Cys). This variant is present in population databases (rs28940869, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of muscle-eye-brain disease (PMID: 15236414, 17906881). It has also been observed to segregate with disease in related individuals. This variant is also known as c.1465C>T. ClinVar contains an entry for this variant (Variation ID: 3992). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects POMGNT1 function (PMID: 21361872). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222337	SCV002500816	pathogenic	Autosomal recessive limb-girdle muscular dystrophy	2022-03-31	criteria provided, single submitter	clinical testing	Variant summary: POMGNT1 c.1324C>T (p.Arg442Cys) 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 was absent in 251304 control chromosomes (gnomAD). c.1324C>T has been reported in the literature in multiple individuals affected with muscle-eye-brain disease (e.g. Hehr_2007, Voglmeir_2011, Khan_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to be not active (Voglmeir_2011). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV002512738	SCV003761169	likely pathogenic	Muscular dystrophy-dystroglycanopathy	2023-01-24	criteria provided, single submitter	curation	The p.Arg442Cys variant in POMGNT1 has been reported in four individuals with muscular dystrophy-dystroglycanopathy (PMID: 25390965, 17906881, 15236414), segregated with disease in 2 affected relatives from 2 families (PMID: 17906881, 15236414), and has been identified in 0.006% (1/15428) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID:rs28940869). 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#:3992) and has been interpreted as pathogenic/likely pathogenic by OMIM, GeneDx, Invitae, Baylor Genetics, Women's Health and Genetics/Laboratory Corporation of America, LabCorp, Eurofins NTD LLC (GA), Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics), Athena Diagnostics Inc., and Counsyl. Of these four affected individuals, two were homozygotes, which increases the likelihood that the p.Arg442Cys variant is pathogenic (PMID: 17906881). In vitro functional studies provide some evidence that the p.Arg442Cys variant may impact protein function, as reflected by reduced catalytic activity in enzymatic activity assays (PMID: 21361872). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg442His, has been reported in association with disease in ClinVar, slightly supporting that a change at this position may not be tolerated (Variation ID: 872288). 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: PS3_supporting, PM2_Supporting, PM3, PM5_Supporting, PP3, PP1 (Richards 2015).
Baylor Genetics	RCV001847573	SCV004205974	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2023-08-04	criteria provided, single submitter	clinical testing
OMIM	RCV001847573	SCV000024365	pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3	2004-07-01	no assertion criteria provided	literature only
Counsyl	RCV000984210	SCV001132277	likely pathogenic	Muscle eye brain disease	2018-10-19	no assertion criteria provided	clinical testing
Counsyl	RCV000984301	SCV001132473	likely pathogenic	Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3	2018-10-19	no assertion criteria provided	clinical testing
Counsyl	RCV000984302	SCV001132474	likely pathogenic	Autosomal recessive limb-girdle muscular dystrophy type 2O	2018-10-19	no assertion criteria provided	clinical testing
Counsyl	RCV000984303	SCV001132475	likely pathogenic	Retinitis pigmentosa 76	2018-10-19	no assertion criteria provided	clinical testing