A compound heterozygous missense variation in exon 4 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at amino acid position 125 was detected. The observed variant c.374C>T (p.Pro125Leu) 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. The allele frequency of the variant is 0.00000399 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000512.5(GALNS):c.374C>T (p.Pro125Leu)
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.
(4)
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
4
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.374C>T (p.Pro125Leu)
Variation ID: 873151 Accession: VCV000873151.13
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 16q24.3 16: 88841040 (GRCh38) [ NCBI UCSC ] 16: 88907448 (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 May 31, 2020 Feb 14, 2024 Dec 13, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000512.5:c.374C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000503.1:p.Pro125Leu missense NM_001323543.2:c.-182C>T 5 prime UTR NM_001323544.2:c.392C>T NP_001310473.1:p.Pro131Leu missense NC_000016.10:g.88841040G>A NC_000016.9:g.88907448G>A NG_008667.1:g.20927C>T - Protein change
- P125L, P131L
- Other names
- -
- Canonical SPDI
- NC_000016.10:88841039:G:A
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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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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- 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 (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 13, 2023 | RCV001095388.13 |
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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|---|---|---|---|---|---|
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Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190351.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
A compound heterozygous missense variation in exon 4 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at amino … (more)
A compound heterozygous missense variation in exon 4 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at amino acid position 125 was detected. The observed variant c.374C>T (p.Pro125Leu) 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. The allele frequency of the variant is 0.00000399 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic. (less)
Clinical Features:
Beaking of vertebral bodies (present) , Short stature (present)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Indian 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)
|
criteria provided, single submitter
Method: research
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: yes
Allele origin:
germline
|
Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova
Accession: SCV001547671.3
First in ClinVar: Aug 25, 2021 Last updated: Oct 30, 2021 |
Comment:
In vitro and in vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; low to … (more)
In vitro and in 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_moderate); 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)
|
|
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Pathogenic
(Dec 13, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001386062.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the GALNS protein (p.Pro125Leu). … (more)
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the GALNS protein (p.Pro125Leu). This variant is present in population databases (rs746949976, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9375852, 15241807, 24035930, 30458289). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 873151). 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%. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Mar 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-A
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811697.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
Comment:
Comment:
In vitro and in 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_moderate); 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:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the GALNS protein (p.Pro125Leu). This variant is present in population databases (rs746949976, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9375852, 15241807, 24035930, 30458289). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 873151). 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%. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). For these reasons, this variant has been classified as Pathogenic.
Germline Functional Evidence
| Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
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
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|---|---|---|---|
|
Unknown function
|
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001190351.1
|
|
Comment:
A compound heterozygous missense variation in exon 4 of the GALNS gene that results in the amino acid substitution of Leucine for Proline at amino acid position 125 was detected. The observed variant c.374C>T (p.Pro125Leu) 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. The allele frequency of the variant is 0.00000399 in gnomAD Exomes. In summary, the variant meets our criteria to be classified as likely pathogenic.
Comment:
In vitro and in 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_moderate); 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:
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 125 of the GALNS protein (p.Pro125Leu). This variant is present in population databases (rs746949976, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 9375852, 15241807, 24035930, 30458289). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 873151). 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%. Experimental studies have shown that this missense change affects GALNS function (PMID: 10814710). For these reasons, this variant has been 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 |
| Mutation analysis and pathogenicity identification of Mucopolysaccharidosis type IVA in 8 south China families. | Xie J | Gene | 2019 | PMID: 30458289 |
| Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations. | Caciotti A | Human mutation | 2015 | PMID: 25545067 |
| Molecular genetic assay of mucopolysaccharidosis IVA in South China. | He D | Gene | 2013 | PMID: 24035930 |
| Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. | Dũng VC | Molecular genetics and metabolism | 2013 | PMID: 23876334 |
| [Identification of a novel mutation of GALNS gene from a Chinese pedigree with mucopolysaccharidosis type IV A]. | Zhao Y | Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics | 2011 | PMID: 21644215 |
| Mucopolysaccharidosis IVA (Morquio A): identification of novel common mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene in Italian patients. | Tomatsu S | Human mutation | 2004 | PMID: 15241807 |
| 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 |
| Fourteen novel mucopolysaccharidosis IVA producing mutations in GALNS gene. | Tomatsu S | Human mutation | 1997 | PMID: 9375852 |
| https://doi.org/10.1016/j.mgene.2018.01.008; | - | - | - | - |
Text-mined citations for rs746949976 ...
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.