ClinVar Genomic variation as it relates to human health
NM_017739.4(POMGNT1):c.1469G>A (p.Cys490Tyr)
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.1469G>A (p.Cys490Tyr)
Variation ID: 4000 Accession: VCV000004000.39
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 1p34.1 1: 46192168 (GRCh38) [ NCBI UCSC ] 1: 46657840 (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 Jan 6, 2017 May 12, 2024 Feb 14, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_017739.4:c.1469G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_060209.4:p.Cys490Tyr missense NM_001243766.1:c.1469G>A NM_001243766.2:c.1469G>A NP_001230695.2:p.Cys490Tyr missense NM_001290129.2:c.1403G>A NP_001277058.2:p.Cys468Tyr missense NM_001290130.2:c.1040G>A NP_001277059.2:p.Cys347Tyr missense NC_000001.11:g.46192168C>T NC_000001.10:g.46657840C>T NG_009205.3:g.33138G>A LRG_701:g.33138G>A LRG_701t1:c.1469G>A LRG_701p1:p.Cys490Tyr LRG_701t2:c.1469G>A LRG_701p2:p.Cys490Tyr Q8WZA1:p.Cys490Tyr - Protein change
- C490Y, C347Y, C468Y
- Other names
- NM_017739.4(POMGNT1):c.1469G>A
- Canonical SPDI
- NC_000001.11:46192167:C:T
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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.
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
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 (1) |
no assertion criteria provided
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Jan 1, 2008 | RCV000004207.12 | |
Likely pathogenic (2) |
criteria provided, single submitter
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Oct 17, 2016 | RCV000411094.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 18, 2024 | RCV000798530.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 10, 2023 | RCV001091843.27 | |
Pathogenic (1) |
criteria provided, single submitter
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Jul 27, 2021 | RCV002476922.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jan 24, 2023 | RCV002512742.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 16, 2023 | RCV003460424.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2024 | RCV004532285.1 |
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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Likely pathogenic
(Oct 17, 2016)
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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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Counsyl
Accession: SCV000487167.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Pathogenic
(Jul 27, 2021)
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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
Muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B3 Autosomal recessive limb-girdle muscular dystrophy type 2O Retinitis pigmentosa 76
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894031.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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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: SCV003761162.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
Comment:
The p.Cys490Tyr variant in POMGNT1 has been reported in 8 individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 15466003, 22323514, 17559086, 24282183, 17030669), and has been identified … (more)
The p.Cys490Tyr variant in POMGNT1 has been reported in 8 individuals with POMGNT1-associated muscular dystrophy-dystroglycanopathy (PMID: 15466003, 22323514, 17559086, 24282183, 17030669), and has been identified in 0.006% (2/35440) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: dbSNP ID rs267606960). 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 #4000) and has been interpreted as pathogenic by Invitae, Fulgent Genetics, CeGaT Center for Human Genetics Tuebingen, OMIM, and Natera, Inc, and as likely pathogenic by PerkinElmer Genomics and Counsyl. Of these 8 affected individuals, 3 were homozygotes, and at least 1 was a compound heterozygote that carried a pathogenic variant in trans, which increases the likelihood that the p.Cys490Tyr variant is pathogenic (PMID: 15466003, 22323514, 17559086, 24282183; ClinvarID: 265399). In vitro functional studies provide some evidence that the p.Cys490Tyr variant may impact protein function, as reflected by reduced catalytic activity in an in vitro enzymatic activity assay (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. 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: PM3_Strong, PM2_supporting, PS3_Supporting, PP3 (Richards 2015). (less)
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Likely pathogenic
(Mar 25, 2021)
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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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Revvity Omics, Revvity
Accession: SCV002024719.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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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: SCV000938150.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 490 of the POMGNT1 protein … (more)
This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 490 of the POMGNT1 protein (p.Cys490Tyr). This variant is present in population databases (rs267606960, gnomAD 0.006%). This missense change has been observed in individual(s) with congenital muscular dystrophy, cobblestone lissencephaly, and muscle-eye-brain (MEB) disease (PMID: 15466003, 17030669, 17559086, 17878207, 22323514, 24282183). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4000). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on POMGNT1 protein function. 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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Pathogenic
(Feb 14, 2024)
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criteria provided, single submitter
Method: clinical testing
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POMGNT1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004729494.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The POMGNT1 c.1469G>A variant is predicted to result in the amino acid substitution p.Cys490Tyr. This variant has been reported in homozygous and compound heterozygous states … (more)
The POMGNT1 c.1469G>A variant is predicted to result in the amino acid substitution p.Cys490Tyr. This variant has been reported in homozygous and compound heterozygous states in individuals with POMGNT1-related disorders (Diesen et al. 2004. PubMed ID: 15466003; Raducu et al. 2013. PubMed ID: 24282183; Biancheri et al. 2006. PubMed ID: 17030669; Godfrey et al. 2007. PubMed ID: 17878207; Bouchet et al. 2007. PubMed ID: 17559086). A functional study showed the p.Cys490 substitution does not decrease protein expression, but does cause reduced catalytic activity (Voglmeir et al. 2011. PubMed ID: 21361872). This variant is reported in 0.0056% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Apr 01, 2019)
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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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248089.21
First in ClinVar: May 12, 2020 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 10, 2023)
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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: SCV003926019.1
First in ClinVar: May 27, 2023 Last updated: May 27, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18195152, 17559086, 21361872, 19067344, 15466003, 17906881, 22323514, 24282183, 17878207, 17030669, 31589614) (less)
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Pathogenic
(Oct 16, 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: SCV004205956.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Jan 01, 2008)
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no assertion criteria provided
Method: literature only
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MUSCULAR DYSTROPHY-DYSTROGLYCANOPATHY (CONGENITAL WITH IMPAIRED INTELLECTUAL DEVELOPMENT), TYPE B, 3
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024373.4
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2020 |
Comment on evidence:
See 606822.0015 and Clement et al. (2008).
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Pathogenic
(Sep 16, 2020)
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no assertion criteria provided
Method: clinical testing
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Muscle-eye-brain disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV001460159.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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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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Clinical features and molecular characterization of a patient with muscle-eye-brain disease: a novel mutation in the POMGNT1 gene. | Raducu M | Journal of child neurology | 2014 | PMID: 24282183 |
Cobblestone lissencephaly: neuropathological subtypes and correlations with genes of dystroglycanopathies. | Devisme L | Brain : a journal of neurology | 2012 | PMID: 22323514 |
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 |
Brain involvement in muscular dystrophies with defective dystroglycan glycosylation. | Clement E | Annals of neurology | 2008 | PMID: 19067344 |
Mild POMGnT1 mutations underlie a novel limb-girdle muscular dystrophy variant. | Clement EM | Archives of neurology | 2008 | PMID: 18195152 |
Refining genotype phenotype correlations in muscular dystrophies with defective glycosylation of dystroglycan. | Godfrey C | Brain : a journal of neurology | 2007 | PMID: 17878207 |
Molecular heterogeneity in fetal forms of type II lissencephaly. | Bouchet C | Human mutation | 2007 | PMID: 17559086 |
POMGnT1 mutations in congenital muscular dystrophy: genotype-phenotype correlation and expanded clinical spectrum. | Biancheri R | Archives of neurology | 2006 | PMID: 17030669 |
POMGnT1 mutation and phenotypic spectrum in muscle-eye-brain disease. | Diesen C | Journal of medical genetics | 2004 | PMID: 15466003 |
Text-mined citations for rs267606960 ...
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.