NM_000512.5(GALNS):c.280C>T (p.Arg94Cys) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Dec 19, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000806517.15

Allele description [Variation Report for NM_000512.5(GALNS):c.280C>T (p.Arg94Cys)]

NM_000512.5(GALNS):c.280C>T (p.Arg94Cys)

Gene:

GALNS:galactosamine (N-acetyl)-6-sulfatase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000512.5(GALNS):c.280C>T (p.Arg94Cys)

HGVS:

NC_000016.10:g.88841936G>A
NG_008667.1:g.20031C>T
NM_000512.5:c.280C>TMANE SELECT
NM_001323543.2:c.-276C>T
NM_001323544.2:c.298C>T
NP_000503.1:p.Arg94Cys
NP_001310473.1:p.Arg100Cys
NC_000016.9:g.88908344G>A
NM_000512.4:c.280C>T

Protein change:

R100C

Links:

dbSNP: rs118204441

NCBI 1000 Genomes Browser:

rs118204441

Molecular consequence:

NM_001323543.2:c.-276C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000512.5:c.280C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.298C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-IV-A (MPS4A)
Synonyms:: MORQUIO SYNDROME A; GALACTOSAMINE-6-SULFATASE DEFICIENCY; GALNS DEFICIENCY; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009659; MedGen: C0086651; Orphanet: 309297; Orphanet: 582; OMIM: 253000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000946521	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 19, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 7795586, 9298823, 10814710, 23876334, 29731656, 28492532
SCV001547646	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2021)	germline	research	PubMed (10) [See all records that cite these PMIDs] 16287098, 23876334, 24726177, 25545067, 29731656, 30094185, 7795586, 8826435, 34387910, 25741868
SCV002024159	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045034	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002803365	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 7, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome.

Bunge S, Kleijer WJ, Tylki-Szymanska A, Steglich C, Beck M, Tomatsu S, Fukuda S, Poorthuis BJ, Czartoryska B, Orii T, Gal A.

Hum Mutat. 1997;10(3):223-32.

PubMed [citation]

PMID:: 9298823

Biochemical and structural analysis of missense mutations in N-acetylgalactosamine-6-sulfate sulfatase causing mucopolysaccharidosis IVA phenotypes.

Sukegawa K, Nakamura H, Kato Z, Tomatsu S, Montaño AM, Fukao T, Toietta G, Tortora P, Orii T, Kondo N.

Hum Mol Genet. 2000 May 22;9(9):1283-90.

PubMed [citation]

PMID:: 10814710

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000946521.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 94 of the GALNS protein (p.Arg94Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individuals with mucopolysaccharidosis type IVa (PMID: 10814710, 23876334, 29731656). ClinVar contains an entry for this variant (Variation ID: 651205). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 7795586, 10814710). This variant disrupts the p.Arg94 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been observed in individuals with GALNS-related conditions (PMID: 7795586, 9298823, 10814710, 23876334, 29731656), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547646.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (10)

Description

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_moderate); 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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002024159.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002045034.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002803365.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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