ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.230C>G (p.Pro77Arg)
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_000512.5(GALNS):c.230C>G (p.Pro77Arg)
Variation ID: 856567 Accession: VCV000856567.16
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 88842720 (GRCh38) [ NCBI UCSC ] 16: 88909128 (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 Apr 15, 2020 Feb 14, 2024 Dec 13, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000512.5:c.230C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Pro77Arg missense NM_001323543.2:c.-311-749C>G intron variant NM_001323544.2:c.248C>G NP_001310473.1:p.Pro83Arg missense NC_000016.10:g.88842720G>C NC_000016.9:g.88909128G>C NG_008667.1:g.19247C>G - Protein change
- P83R, P77R
- Other names
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- Canonical SPDI
- NC_000016.10:88842719:G:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Unknown function
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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.
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- 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 |
1054 | 1341 |
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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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Oct 26, 2022 | RCV001062057.15 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 13, 2022 | RCV003235459.1 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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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Likely pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190349.1
First in ClinVar: May 19, 2020 Last updated: May 19, 2020 |
Comment:
A Homozygous missense variation in exon 2 of the GALNS gene that results in the amino acid substitution of Arginine for Proline at codon 77 … (more)
A Homozygous missense variation in exon 2 of the GALNS gene that results in the amino acid substitution of Arginine for Proline at codon 77 was detected. The observed variant c.230C>G (p.Pro77Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is damaging by LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Genu valgum (present) , Frontal bossing (present) , Corneal opacity (present) , Short neck (present) , Kyphosis (present) , Motor delay (present)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Gujarati/Hindu
Geographic origin: India
Method: Sanger sequencing using custom designed primers that targeted exonic regions of the GALNS gene.
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Likely pathogenic
(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: SCV001547622.3
First in ClinVar: Aug 25, 2021 Last updated: Oct 30, 2021 |
Comment:
In vitro and vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null … (more)
In vitro and vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to null in vitro enzymatic activity; PS3_strong); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); absent from 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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Likely pathogenic
(Nov 07, 2021)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002045038.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
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Likely pathogenic
(Mar 17, 2022)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002792298.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Dec 13, 2022)
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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: SCV003933621.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 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: 22940367, 7633425, 25287660, 25501214, 30980944, 24726177, 15235041, 23876334, 32183856, 34387910, Sheth[article]2020) (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Mucopolysaccharidosis, MPS-IV-A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004101537.1
First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023 |
Comment:
The missense variant c.230C>G (p.Pro77Arg) in GALNS gene has been observed in several individuals affected with mucopolysaccharidosis type IV(Dung VC et.al.,2013). This variant has been … (more)
The missense variant c.230C>G (p.Pro77Arg) in GALNS gene has been observed in several individuals affected with mucopolysaccharidosis type IV(Dung VC et.al.,2013). This variant has been reported to affect GALNS protein function (Sukegawa K et.al.,2000). This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic. The p.Pro77Arg variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Pro at position 77 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Functional motor deficit (present) , Genu valgum (present) , Short stature (present) , Corneal opacity (present) , Pectus carinatum (present) , Abnormal pelvis bone morphology … (more)
Functional motor deficit (present) , Genu valgum (present) , Short stature (present) , Corneal opacity (present) , Pectus carinatum (present) , Abnormal pelvis bone morphology (present) , Abnormal brain morphology (present) , Platyspondyly (present) , Abnormal digit morphology (present) , Decreased beta-galactosidase activity (present) (less)
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Pathogenic
(Oct 26, 2022)
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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: SCV001226829.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the … (more)
This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Pro77 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 25252036), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). 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: 856567). This missense change has been observed in individuals with mucopolysaccharidosis type IVA (MPS IVA) (PMID: 7633425, 15235041, 23876334; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 77 of the GALNS protein (p.Pro77Arg). (less)
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Germline Functional Evidence
Functional
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The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
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A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
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A brief description of the result of this method for 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
Help
This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190349.1
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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 |
Mutation spectrum and pivotal features for differential diagnosis of Mucopolysaccharidosis IVA patients with severe and attenuated phenotype. | Tüysüz B | Gene | 2019 | PMID: 30980944 |
GALNS mutations in Indian patients with mucopolysaccharidosis IVA. | Bidchol AM | American journal of medical genetics. Part A | 2014 | PMID: 25252036 |
Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. | Morrone A | Molecular genetics and metabolism | 2014 | PMID: 24726177 |
Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. | Dũng VC | Molecular genetics and metabolism | 2013 | PMID: 23876334 |
Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene. | Tomatsu S | Journal of medical genetics | 2004 | PMID: 15235041 |
Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes. | Sukegawa K | Human molecular genetics | 2000 | PMID: 10814710 |
Mucopolysaccharidosis type IVA: identification of six novel mutations among non-Japanese patients. | Tomatsu S | Human molecular genetics | 1995 | PMID: 7633425 |
Text-mined citations for rs1422505598 ...
HelpRecord last updated Apr 06, 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.