In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 800974). This variant has been observed in individuals with clinical features of mucopolysaccaridosis type IVA (PMID: 24726177, 32860008). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 492 of the GALNS protein (p.Ala492Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.1474G>A (p.Ala492Thr)
Germline
Classification
Help
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.
(7)
Help
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/Likely pathogenic
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000512.5(GALNS):c.1474G>A (p.Ala492Thr)
Variation ID: 800974 Accession: VCV000800974.16
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q24.3 16: 88818015 (GRCh38) [ NCBI UCSC ] 16: 88884423 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 4, 2020 Apr 20, 2024 Mar 17, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000512.5:c.1474G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Ala492Thr missense NM_001323543.2:c.919G>A NP_001310472.1:p.Ala307Thr missense NM_001323544.2:c.1492G>A NP_001310473.1:p.Ala498Thr missense NC_000016.10:g.88818015C>T NC_000016.9:g.88884423C>T NG_008667.1:g.43952G>A - Protein change
- A492T, A498T, A307T
- Other names
- -
- Canonical SPDI
- NC_000016.10:88818014:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00000
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| GALNS | - | - |
GRCh38 GRCh37 |
1083 | 1377 | |
| LOC126862447 | - | - | - | GRCh38 | - | 122 |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2024 | RCV000985198.16 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Aug 26, 2022 | RCV004017767.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001426497.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
|
|
|
Likely pathogenic
(Nov 07, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002044936.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Likely pathogenic
(Jun 23, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002311143.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has … (more)
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 800974). This variant has been observed in individuals with clinical features of mucopolysaccaridosis type IVA (PMID: 24726177, 32860008). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 492 of the GALNS protein (p.Ala492Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. (less)
|
|
|
Likely pathogenic
(Mar 17, 2024)
|
criteria provided, single submitter
Method: research
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center
Accession: SCV004804741.2
First in ClinVar: Mar 30, 2024 Last updated: Apr 06, 2024 |
|
|
|
Likely Pathogenic
(Aug 26, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Morquio syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848736.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Ala492Thr in GALNS has been reported in 1 homozygous and 1 compound heterozygous invidivuals with mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A) … (more)
The p.Ala492Thr in GALNS has been reported in 1 homozygous and 1 compound heterozygous invidivuals with mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A) (Morrone 2014 PMID: 24726177, Bertoli-Avella 2021 PMID: 32860008), and was absent in large population databases. Measurement of GALNS activity from leukocytes or cultured fibroblasts from the homozygous patient above showed low to absent activity (Morrone 2014 PMID: 24726177). 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 meets criteria to be classified as likely pathogenic for MPS IVA in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3, PP3. (less)
|
|
|
Pathogenic
(Sep 26, 2019)
|
no assertion criteria provided
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
|
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001133223.1
First in ClinVar: Jan 04, 2020 Last updated: Jan 04, 2020 |
|
|
|
Uncertain significance
(Feb 01, 2021)
|
Flagged submission
flagged submission
Method: research
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV001547975.3
First in ClinVar: Aug 25, 2021 Last updated: Oct 30, 2021 |
Comment:
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 … (more)
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) (less)
|
|
| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Comment:
Comment:
The p.Ala492Thr in GALNS has been reported in 1 homozygous and 1 compound heterozygous invidivuals with mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A) (Morrone 2014 PMID: 24726177, Bertoli-Avella 2021 PMID: 32860008), and was absent in large population databases. Measurement of GALNS activity from leukocytes or cultured fibroblasts from the homozygous patient above showed low to absent activity (Morrone 2014 PMID: 24726177). 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 meets criteria to be classified as likely pathogenic for MPS IVA in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3, PP3.
Comment:
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
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. |
Comment:
In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: 800974). This variant has been observed in individuals with clinical features of mucopolysaccaridosis type IVA (PMID: 24726177, 32860008). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with threonine at codon 492 of the GALNS protein (p.Ala492Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine.
Comment:
The p.Ala492Thr in GALNS has been reported in 1 homozygous and 1 compound heterozygous invidivuals with mucopolysaccharidosis type 4A (MPS IVA, aka Morquio syndrome A) (Morrone 2014 PMID: 24726177, Bertoli-Avella 2021 PMID: 32860008), and was absent in large population databases. Measurement of GALNS activity from leukocytes or cultured fibroblasts from the homozygous patient above showed low to absent activity (Morrone 2014 PMID: 24726177). 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 meets criteria to be classified as likely pathogenic for MPS IVA in an autosomal recessive manner. ACMG/AMP Criteria applied: PM3, PM2_Supporting, PS3, PP3.
Comment:
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Successful application of genome sequencing in a diagnostic setting: 1007 index cases from a clinically heterogeneous cohort. | Bertoli-Avella AM | European journal of human genetics : EJHG | 2021 | PMID: 32860008 |
| Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. | Morrone A | Molecular genetics and metabolism | 2014 | PMID: 24726177 |
Text-mined citations for rs760300454 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.