This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.1019G>A (p.Gly340Asp)
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.1019G>A (p.Gly340Asp)
Variation ID: 18403 Accession: VCV000018403.13
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 16q24.3 16: 88826822 (GRCh38) [ NCBI UCSC ] 16: 88893230 (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 Jun 2, 2018 Feb 14, 2024 Nov 1, 2023 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000512.5:c.1019G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Gly340Asp missense NM_000512.4:c.1019G>A NM_001323543.2:c.464G>A NP_001310472.1:p.Gly155Asp missense NM_001323544.2:c.1037G>A NP_001310473.1:p.Gly346Asp missense NC_000016.10:g.88826822C>T NC_000016.9:g.88893230C>T NG_008667.1:g.35145G>A P34059:p.Gly340Asp - Protein change
- G340D, G346D, G155D
- Other names
- -
- Canonical SPDI
- NC_000016.10:88826821: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.
-
Trans-Omics for Precision Medicine (TOPMed) 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 | |
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
|
Nov 1, 2023 | RCV000000750.15 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 27, 2023 | RCV003155036.1 |
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. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Jul 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
MUCOPOLYSACCHARIDOSIS, TYPE IVA
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV001984834.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is … (more)
This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic. (less)
|
|
|
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: SCV002045002.1
First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022 |
|
|
|
Pathogenic
(Nov 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001591345.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein … (more)
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
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: SCV001426611.1
First in ClinVar: Aug 09, 2020 Last updated: Aug 09, 2020 |
|
|
|
Pathogenic
(Feb 01, 2021)
|
criteria provided, single submitter
Method: curation
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV001547876.3
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_strong);the prevalence of the variant … (more)
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong);the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting) (less)
|
|
|
Pathogenic
(Feb 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Morquio syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844258.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of the encoded protein sequence. Five … (more)
Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of 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 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Pathogenic
(Aug 01, 2010)
|
no assertion criteria provided
Method: literature only
|
MUCOPOLYSACCHARIDOSIS, TYPE IVA
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000020900.3
First in ClinVar: Apr 04, 2013 Last updated: Jun 02, 2018 |
Comment on evidence:
In 5 of 24 Chinese patients with MPS IVA (253000), Wang et al. (2010) identified a 1019G-A transition in exon 10 of the GALNS gene, … (more)
In 5 of 24 Chinese patients with MPS IVA (253000), Wang et al. (2010) identified a 1019G-A transition in exon 10 of the GALNS gene, resulting in a gly340-to-asp (G340D) substitution. Three patients were homozygous, and 2 patients were compound heterozygous for G340D and another mutation. G340D was the most common mutant allele, accounting for 16.7% of the total number of mutant alleles. Haplotype analysis indicated a founder effect, and all 5 patients were residents of or emigrants from central eastern China. (less)
|
Comment:
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong);the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Comment:
Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of 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 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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:
This variant has been previously reported as a compound heterozygous and homozygous change in patients with Mucopolysaccharidosis IVA (PMID: 20574428, 15235041, 30980944, 30458289). It is absent from the gnomAD population database and thus is presumed to be rare. The c.1019G>A (p.Gly340Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1019G>A (p.Gly340Asp) variant is classified as Likely Pathogenic.
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 340 of the GALNS protein (p.Gly340Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 15235041, 20574428, 30458289, 30980944). ClinVar contains an entry for this variant (Variation ID: 18403). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Comment:
In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong);the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_strong); absent from gnomAD v2.1.1 (PM2_moderate); multiple lines of computational evidence support a deleterious effect on the gene (PP3_supporting)
Comment:
Variant summary: GALNS c.1019G>A (p.Gly340Asp) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of 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 192834 control chromosomes. c.1019G>A has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type IVA (Tomatsu_2004, Wang_2010, Cozma_2015), and some are reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is very likely to be associated with disease. At least one publication reports quantification of GALNS enzymatic product using blood samples from MPS IVA affected patients and normal controls, finding that samples from patients homozygous with the variant showed a nearly complete loss of activity (Cozma_2015). Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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 |
| Newborn screening for Morquio disease and other lysosomal storage diseases: results from the 8-plex assay for 70,000 newborns. | Chien YH | Orphanet journal of rare diseases | 2020 | PMID: 32014045 |
| Mutation spectrum and pivotal features for differential diagnosis of Mucopolysaccharidosis IVA patients with severe and attenuated phenotype. | Tüysüz B | Gene | 2019 | PMID: 30980944 |
| Mutation analysis and pathogenicity identification of Mucopolysaccharidosis type IVA in 8 south China families. | Xie J | Gene | 2019 | PMID: 30458289 |
| Diagnosis of Morquio Syndrome in Dried Blood Spots Based on a New MRM-MS Assay. | Cozma C | PloS one | 2015 | PMID: 26147980 |
| Molecular genetic assay of mucopolysaccharidosis IVA in South China. | He D | Gene | 2013 | PMID: 24035930 |
| Mucopolysaccharidosis IVA mutations in Chinese patients: 16 novel mutations. | Wang Z | Journal of human genetics | 2010 | PMID: 20574428 |
| Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene. | Tomatsu S | Journal of medical genetics | 2004 | PMID: 15235041 |
Text-mined citations for rs267606838 ...
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 Sep 29, 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.