rs28940869

Positions:

chr1-46192397-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000371984.8(POMGNT1):c.1324C>T(p.Arg442Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R442H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

POMGNT1
ENST00000371984.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 4.53

Variant links:

Genes affected

POMGNT1 (HGNC:19139): (protein O-linked mannose N-acetylglucosaminyltransferase 1 (beta 1,2-)) This gene encodes a type II transmembrane protein that resides in the Golgi apparatus. It participates in O-mannosyl glycosylation and is specific for alpha linked terminal mannose. Mutations in this gene may be associated with muscle-eye-brain disease and several congenital muscular dystrophies. Alternatively spliced transcript variants that encode different protein isoforms have been described. [provided by RefSeq, Feb 2014]

POMGNT1 links:

TSPAN1 (HGNC:):

TSPAN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000371984.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-46192396-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 872288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 1-46192397-G-A is Pathogenic according to our data. Variant chr1-46192397-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3992.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-46192397-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-46192397-G-A is described in Lovd as [Pathogenic]. Variant chr1-46192397-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POMGNT1	NM_017739.4 linkuse as main transcript	c.1324C>T	p.Arg442Cys	missense_variant	16/22	ENST00000371984.8	NP_060209.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POMGNT1	ENST00000371984.8 linkuse as main transcript	c.1324C>T	p.Arg442Cys	missense_variant	16/22	1	NM_017739.4	ENSP00000361052	P1	Q8WZA1-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152162

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 21, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2017	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 21, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 20, 2017	- -

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 2004	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -

Muscle eye brain disease

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Oct 19, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

Autosomal recessive limb-girdle muscular dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 31, 2022

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. -

Muscular dystrophy-dystroglycanopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Jan 24, 2023

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). -

Retinitis pigmentosa 76

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 19, 2018

- -

Autosomal recessive limb-girdle muscular dystrophy type 2O

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 19, 2018

- -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3;C3150417:Autosomal recessive limb-girdle muscular dystrophy type 2O

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 09, 2023

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. -

Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Counsyl

Oct 19, 2018

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.29

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

3.6

H;H

MutationTaster

Benign

1.0

A;A;A;A;A

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.98

MutPred

0.98

Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);

MVP

0.98

MPC

1.1

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over