ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.1157G>A (p.Arg386His)
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.
Pathogenic(2); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000512.5(GALNS):c.1157G>A (p.Arg386His)
Variation ID: 1048232 Accession: VCV001048232.5
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 88824852 (GRCh38) [ NCBI UCSC ] 16: 88891260 (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 Aug 25, 2021 Feb 14, 2024 Sep 9, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000512.5:c.1157G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Arg386His missense NM_000512.4:c.1157G>A NM_001323543.2:c.602G>A NP_001310472.1:p.Arg201His missense NM_001323544.2:c.1175G>A NP_001310473.1:p.Arg392His missense NC_000016.10:g.88824852C>T NC_000016.9:g.88891260C>T NG_008667.1:g.37115G>A - Protein change
- R201H, R386H, R392H
- Other names
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- Canonical SPDI
- NC_000016.10:88824851: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
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD) 0.00002
- Links
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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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GALNS | - | - |
GRCh38 GRCh37 |
1079 | 1372 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Sep 9, 2023 | RCV001578334.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 14, 2022 | RCV002469379.1 |
Submissions - Germline
Classification
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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
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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
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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
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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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Uncertain significance
(Feb 01, 2021)
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criteria provided, single submitter
Method: curation
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Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV001547908.3
First in ClinVar: Aug 25, 2021 Last updated: Oct 30, 2021 |
Comment:
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate); … (more)
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_moderate); very low frequency in gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) (less)
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Pathogenic
(Nov 14, 2022)
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criteria provided, single submitter
Method: clinical testing
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Morquio syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002766060.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Variant summary: GALNS c.1157G>A (p.Arg386His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more)
Variant summary: GALNS c.1157G>A (p.Arg386His) results in a non-conservative amino acid change in the encoded protein sequence. Four 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-06 in 249400 control chromosomes. c.1157G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Mucopolysaccharidosis Type IVA (Morquio Syndrome A) (example, Tomatzu_2004, Pintos-Morell_2018, Tuysuz_2019, Moisan_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been ascertained in this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Sep 09, 2023)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004297061.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts … (more)
This variant is present in population databases (no rsID available, gnomAD 0.002%). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg386 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7795586, 9298823, 15309681, 22976768, 23227063, 24726177, 26147980). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 GALNS protein function. ClinVar contains an entry for this variant (Variation ID: 1048232). This variant is also known as c.1158G>A (p.R386H). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15309681). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 386 of the GALNS protein (p.Arg386His). (less)
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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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Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants. | Zanetti A | Human mutation | 2021 | PMID: 34387910 |
Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study. | Moisan L | Orphanet journal of rare diseases | 2020 | PMID: 32993725 |
Mutation spectrum and pivotal features for differential diagnosis of Mucopolysaccharidosis IVA patients with severe and attenuated phenotype. | Tüysüz B | Gene | 2019 | PMID: 30980944 |
Elosulfase alfa for mucopolysaccharidosis type IVA: Real-world experience in 7 patients from the Spanish Morquio-A early access program. | Pintos-Morell G | Molecular genetics and metabolism reports | 2018 | PMID: 30023300 |
Diagnosis of Morquio Syndrome in Dried Blood Spots Based on a New MRM-MS Assay. | Cozma C | PloS one | 2015 | PMID: 26147980 |
Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. | Morrone A | Molecular genetics and metabolism | 2014 | PMID: 24726177 |
Molecular characterization of 355 mucopolysaccharidosis patients reveals 104 novel mutations. | Pollard LM | Journal of inherited metabolic disease | 2013 | PMID: 22976768 |
Clinical, radiologic, and genetic features of Korean patients with Mucopolysaccharidosis IVA. | Lee NH | Korean journal of pediatrics | 2012 | PMID: 23227063 |
The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A. | Rivera-Colón Y | Journal of molecular biology | 2012 | PMID: 22940367 |
Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate. | Tomatsu S | Journal of human genetics | 2004 | PMID: 15309681 |
Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome. | Bunge S | Human mutation | 1997 | PMID: 9298823 |
Mucopolysaccharidosis IVA: screening and identification of mutations of the N-acetylgalactosamine-6-sulfate sulfatase gene. | Ogawa T | Human molecular genetics | 1995 | PMID: 7795586 |
https://doi.org/10.1016/j.mgene.2018.01.008 | - | - | - | - |
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Text-mined citations for rs1221167717 ...
HelpRecord last updated Jun 17, 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.