ClinVar Genomic variation as it relates to human health
NM_017739.4(POMGNT1):c.1324C>T (p.Arg442Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_017739.4(POMGNT1):c.1324C>T (p.Arg442Cys)
Variation ID: 3992 Accession: VCV000003992.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 46192397 (GRCh38) [ NCBI UCSC ] 1: 46658069 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline May 29, 2016 Feb 28, 2024 Dec 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017739.4:c.1324C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060209.4:p.Arg442Cys missense NM_001243766.2:c.1324C>T NP_001230695.2:p.Arg442Cys missense NM_001290129.2:c.1258C>T NP_001277058.2:p.Arg420Cys missense NM_001290130.2:c.895C>T NP_001277059.2:p.Arg299Cys missense NC_000001.11:g.46192397G>A NC_000001.10:g.46658069G>A NG_009205.3:g.32909C>T LRG_701:g.32909C>T LRG_701t1:c.1324C>T LRG_701p1:p.Arg442Cys LRG_701t2:c.1324C>T LRG_701p2:p.Arg442Cys Q8WZA1:p.Arg442Cys - Protein change
- R442C, R420C, R299C
- Other names
- p.R442C:CGT>TGT
- NM_017739.4(POMGNT1):c.1324C>T
- Canonical SPDI
- NC_000001.11:46192396:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD) 0.00004
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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POMGNT1 | - | - |
GRCh38 GRCh37 |
257 | 1410 | |
TSPAN1 | - | - |
GRCh38 GRCh37 |
13 | 1145 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2017 | RCV000150001.16 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 19, 2018 | RCV000984302.9 | |
Pathogenic (2) |
criteria provided, single submitter
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- | RCV000984210.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 19, 2018 | RCV000984301.9 | |
Likely pathogenic (1) |
no assertion criteria provided
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Oct 19, 2018 | RCV000984303.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 9, 2023 | RCV001219572.12 | |
Pathogenic (2) |
criteria provided, single submitter
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Aug 4, 2023 | RCV001847573.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 31, 2022 | RCV002222337.9 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002512738.9 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000281499.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Pathogenic
(May 11, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000196861.13
First in ClinVar: Jan 23, 2015 Last updated: Dec 15, 2018 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3
Affected status: unknown
Allele origin:
germline
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Baylor Genetics
Accession: SCV001162922.1
First in ClinVar: Feb 29, 2020 Last updated: Feb 29, 2020 |
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Pathogenic
(Mar 31, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002500816.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Jan 24, 2023)
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criteria provided, single submitter
Method: curation
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Muscular dystrophy-dystroglycanopathy
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
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Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Accession: SCV003761169.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
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 … (more)
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). (less)
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Pathogenic
(Dec 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2O
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001391518.4
First in ClinVar: Jul 16, 2020 Last updated: Feb 28, 2024 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Dec 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics
Accession: SCV000843376.1
First in ClinVar: May 29, 2016 Last updated: May 29, 2016 |
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Pathogenic
(Aug 21, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331827.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Aug 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004205974.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jul 01, 2004)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH BRAIN AND EYE ANOMALIES), TYPE A, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024365.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 23, 2016 |
Comment on evidence:
In 2 affected sibs from a non-Finnish family with muscle-eye-brain disease (MDDGA3; 253280), Vervoort et al. (2004) identified compound heterozygosity for 2 mutations in the … (more)
In 2 affected sibs from a non-Finnish family with muscle-eye-brain disease (MDDGA3; 253280), Vervoort et al. (2004) identified compound heterozygosity for 2 mutations in the POMGNT1 gene: a 1465C-T transition in exon 16, resulting in an arg442-to-cys (R442C) substitution, and a 1073G-A transition in exon 10, resulting in an arg311-to-gln substitution (R311Q; 606822.0008). The R442C and R311Q mutations are in the highly conserved GNT1 domain of the protein. Each parent was heterozygous for 1 of the mutations. (less)
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Likely pathogenic
(Oct 19, 2018)
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no assertion criteria provided
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A3
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132277.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Oct 19, 2018)
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no assertion criteria provided
Method: clinical testing
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Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132473.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Oct 19, 2018)
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no assertion criteria provided
Method: clinical testing
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Autosomal recessive limb-girdle muscular dystrophy type 2O
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132474.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Likely pathogenic
(Oct 19, 2018)
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no assertion criteria provided
Method: clinical testing
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Retinitis pigmentosa 76
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132475.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Novel retinal findings in an infant with muscle-eye-brain disease. | Khan M | Retinal cases & brief reports | 2012 | PMID: 25390965 |
Biochemical correlation of activity of the α-dystroglycan-modifying glycosyltransferase POMGnT1 with mutations in muscle-eye-brain disease. | Voglmeir J | The Biochemical journal | 2011 | PMID: 21361872 |
Novel POMGnT1 mutations define broader phenotypic spectrum of muscle-eye-brain disease. | Hehr U | Neurogenetics | 2007 | PMID: 17906881 |
Carriers and patients with muscle-eye-brain disease can be rapidly diagnosed by enzymatic analysis of fibroblasts and lymphoblasts. | Vajsar J | Neuromuscular disorders : NMD | 2006 | PMID: 16427280 |
POMGnT1 gene alterations in a family with neurological abnormalities. | Vervoort VS | Annals of neurology | 2004 | PMID: 15236414 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POMGNT1 | - | - | - | - |
Text-mined citations for rs28940869 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.