VCV000265169.51 - ClinVar

NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)

Germline

Classification

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.

(13)

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

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.860C>T (p.Ser287Leu)

Variation ID: 265169 Accession: VCV000265169.51

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 88835251 (GRCh38) [ NCBI UCSC ] 16: 88901659 (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	Oct 10, 2016	Oct 26, 2024	Mar 14, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000512.5:c.860C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000503.1:p.Ser287Leu	missense
NM_001323543.2:c.305C>T	NP_001310472.1:p.Ser102Leu	missense
NM_001323544.2:c.878C>T	NP_001310473.1:p.Ser293Leu	missense
NC_000016.10:g.88835251G>A
NC_000016.9:g.88901659G>A
NG_008667.1:g.26716C>T
	P34059:p.Ser287Leu

... more HGVS ... less HGVS

Protein change

S287L, S102L, S293L

Other names

Canonical SPDI

NC_000016.10:88835250:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

Links

ClinGen: CA8234955 UniProtKB: P34059#VAR_007211 dbSNP: rs770053354 VarSome

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
Gene	OMIM	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	1086	1380

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.
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 1, 2016	RCV000255770.24
Mucopolysaccharidosis, MPS-IV-A	Pathogenic (9)	criteria provided, multiple submitters, no conflicts	Mar 14, 2024	RCV000701162.24
Morquio syndrome	Likely pathogenic (1)	criteria provided, single submitter	Nov 3, 2022	RCV004017572.1

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 (Mar 16, 2015)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321698.7 First in ClinVar: Oct 10, 2016 Last updated: Oct 10, 2016	Comment: The S287L missense variant has been reported previously in association with MPS IVA in a patient with a severe MPS IVA phenotype who was homozygous … (more) The S287L missense variant has been reported previously in association with MPS IVA in a patient with a severe MPS IVA phenotype who was homozygous for the S287L variant (Bunge et al., 1997). Mapping of the S287L variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). Furthermore, S287L is a non-conservative amino acid substitution, which occurs at a position that is highly conserved across species, and missense variants in nearby residues (F284V, N289D, N289S, G290R, G290S) have also been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Therefore, we interpret S287L to be a pathogenic variant. (less)
Pathogenic (Nov 14, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A Affected status: yes Allele origin: unknown	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001366701.2 First in ClinVar: Jul 06, 2020 Last updated: Dec 12, 2020	Comment: This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3.
Pathogenic (Feb 01, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Mucopolysaccharidosis, MPS-IV-A Affected status: yes Allele origin: germline	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova Accession: SCV001547809.3 First in ClinVar: Aug 25, 2021 Last updated: Oct 30, 2021	Publications: PubMed (12) PubMed: 15235041‚ 16287098‚ 22521955‚ 23876334‚ 24726177‚ 25252036‚ 25545067‚ 26147980‚ 29731656‚ 30980944‚ 9298823‚ 34387910 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 … (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); 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)
Pathogenic (Nov 07, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV002045010.1 First in ClinVar: Jan 03, 2022 Last updated: Jan 03, 2022
Pathogenic (Mar 18, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002792927.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Jun 10, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002024156.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000829946.4 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 9298823‚ 15235041‚ 16287098‚ 23876334‚ 25252036‚ 29731656 Comment: This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). … (more) This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). This variant is present in population databases (rs770053354, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IV type A (PMID: 9298823, 15235041, 16287098, 23876334, 25252036, 29731656). 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: 265169). 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 (Mar 14, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Mucopolysaccharidosis, MPS-IV-A Affected status: unknown Allele origin: germline	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center Accession: SCV004801250.2 First in ClinVar: Mar 16, 2024 Last updated: Apr 06, 2024
Likely Pathogenic (Nov 03, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Morquio syndrome Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848819.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Ser287Leu variant in GALNS has been reported in at least 2 homozygous and 2 compound heterozygous individuals with severe mucopolysaccharidosis IVa (Bunge 1997 PMID: … (more) The p.Ser287Leu variant in GALNS has been reported in at least 2 homozygous and 2 compound heterozygous individuals with severe mucopolysaccharidosis IVa (Bunge 1997 PMID: 9298823, Tuysuz 2019 PMID: 30980944, Zanetti 2020 PMID: 32036093). It has also been reported in ClinVar (Variation ID 265169) and identified in 1/41450 African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Mapping of the variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon 2012 PMID: 22940367). In summary, this variant meets criteria to be classified as Likely pathogenic for autosomal recessive mucopolysaccharidosis IVa. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PS3_Supporting, PP4. (less)
Pathogenic (Dec 01, 2016)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001249834.26 First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024	Number of individuals with the variant: 1
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mucopolysaccharidosis, MPS-IV-A (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Neuberg Centre For Genomic Medicine, NCGM Accession: SCV005061243.1 First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024	Comment: The missense c.860C>T (p.Ser287Leu) variant in the GALNS gene has been observed in individual(s) with mucopolysaccharidosis IV type A (Tomatsu, Shunji et al., 2005). Mapping … (more) The missense c.860C>T (p.Ser287Leu) variant in the GALNS gene has been observed in individual(s) with mucopolysaccharidosis IV type A (Tomatsu, Shunji et al., 2005). Mapping of the p.Ser287Leu variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Serine at position 287 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser287Leu in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. (less) Clinical Features: Abnormality of metabolism/homeostasis (present)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin Accession: SCV005380273.1 First in ClinVar: Oct 26, 2024 Last updated: Oct 26, 2024	Clinical Features: Global developmental delay (present)
Pathogenic (Feb 05, 2020)	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: SCV001190762.1 First in ClinVar: Mar 29, 2020 Last updated: Mar 29, 2020
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Comment:

The S287L missense variant has been reported previously in association with MPS IVA in a patient with a severe MPS IVA phenotype who was homozygous for the S287L variant (Bunge et al., 1997). Mapping of the S287L variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). Furthermore, S287L is a non-conservative amino acid substitution, which occurs at a position that is highly conserved across species, and missense variants in nearby residues (F284V, N289D, N289S, G290R, G290S) have also been reported in the Human Gene Mutation Database in association with MPS IVA (Stenson et al., 2014), further supporting the functional importance of this region of the protein. Therefore, we interpret S287L to be a pathogenic variant.

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); very low frequency in 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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). This variant is present in population databases (rs770053354, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IV type A (PMID: 9298823, 15235041, 16287098, 23876334, 25252036, 29731656). 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: 265169). 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:

The p.Ser287Leu variant in GALNS has been reported in at least 2 homozygous and 2 compound heterozygous individuals with severe mucopolysaccharidosis IVa (Bunge 1997 PMID: 9298823, Tuysuz 2019 PMID: 30980944, Zanetti 2020 PMID: 32036093). It has also been reported in ClinVar (Variation ID 265169) and identified in 1/41450 African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Mapping of the variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon 2012 PMID: 22940367). In summary, this variant meets criteria to be classified as Likely pathogenic for autosomal recessive mucopolysaccharidosis IVa. ACMG/AMP Criteria applied: PM3_Strong, PM2_Supporting, PP3, PS3_Supporting, PP4.

Comment:

The missense c.860C>T (p.Ser287Leu) variant in the GALNS gene has been observed in individual(s) with mucopolysaccharidosis IV type A (Tomatsu, Shunji et al., 2005). Mapping of the p.Ser287Leu variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Serine at position 287 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser287Leu in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been 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:

Citations for germline classification of this variant

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 spectrum and pivotal features for differential diagnosis of Mucopolysaccharidosis IVA patients with severe and attenuated phenotype.	Tüysüz B	Gene	2019	PMID: 30980944
Determination of genotypic and clinical characteristics of Colombian patients with mucopolysaccharidosis IVA.	Tapiero-Rodriguez SM	The application of clinical genetics	2018	PMID: 29731656
Diagnosis of Morquio Syndrome in Dried Blood Spots Based on a New MRM-MS Assay.	Cozma C	PloS one	2015	PMID: 26147980
Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations.	Caciotti A	Human mutation	2015	PMID: 25545067
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
Molecular analysis of mucopolysaccharidosis IVA (Morquio A) in Spain.	Pajares S	Molecular genetics and metabolism	2012	PMID: 22521955
Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A).	Tomatsu S	Human mutation	2005	PMID: 16287098
Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene.	Tomatsu S	Journal of medical genetics	2004	PMID: 15235041
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
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Text-mined citations for rs770053354 ...

These 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 27, 2024

ClinVar Genomic variation as it relates to human health

NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs770053354 ...