NM_000512.5(GALNS):c.143T>G (p.Val48Gly) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 15, 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:: RCV001578362.8

Allele description [Variation Report for NM_000512.5(GALNS):c.143T>G (p.Val48Gly)]

NM_000512.5(GALNS):c.143T>G (p.Val48Gly)

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.143T>G (p.Val48Gly)

HGVS:

NC_000016.10:g.88842807A>C
NG_008667.1:g.19160T>G
NM_000512.5:c.143T>GMANE SELECT
NM_001323543.2:c.-311-836T>G
NM_001323544.2:c.161T>G
NP_000503.1:p.Val48Gly
NP_001310473.1:p.Val54Gly
NC_000016.9:g.88909215A>C
NM_000512.4:c.143T>G

Protein change:

V48G

Links:

dbSNP: rs191519947

NCBI 1000 Genomes Browser:

rs191519947

Molecular consequence:

NM_001323543.2:c.-311-836T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000512.5:c.143T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.161T>G - 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
SCV001547604	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 (4) [See all records that cite these PMIDs] 24726177, 32905071, 34387910, 25741868
SCV003259726	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 15, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24726177, 32905071, 34387910, 28492532
SCV004242439	Institute of Human Genetics, University of Leipzig Medical Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Dec 4, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547604

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 (4)
[See all records that cite these PMIDs]

SCV003259726

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 15, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV004242439

Institute of Human Genetics, University of Leipzig Medical Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Dec 4, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Morrone A, Tylee KL, Al-Sayed M, Brusius-Facchin AC, Caciotti A, Church HJ, Coll MJ, Davidson K, Fietz MJ, Gort L, Hegde M, Kubaski F, Lacerda L, Laranjeira F, Leistner-Segal S, Mooney S, Pajares S, Pollard L, Ribeiro I, Wang RY, Miller N.

Mol Genet Metab. 2014 Jun;112(2):160-70. doi: 10.1016/j.ymgme.2014.03.004. Epub 2014 Mar 20. Erratum in: Mol Genet Metab. 2014 Nov;113(3):237.

PubMed [citation]

PMID:: 24726177
PMCID:: PMC4203673

Chondroitin sulfate disaccharide is a specific and sensitive biomarker for mucopolysaccharidosis type IVA.

Chin SJ, Saville JT, McDermott BK, Zankl A, Fletcher JM, Fuller M.

JIMD Rep. 2020 Sep;55(1):68-74. doi: 10.1002/jmd2.12132.

PubMed [citation]

PMID:: 32905071
PMCID:: PMC7463049

See all PubMed Citations (5)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547604.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (4)

Description

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV003259726.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 48 of the GALNS protein (p.Val48Gly). This variant is present in population databases (rs191519947, gnomAD 0.008%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24726177, 32905071, 34387910). ClinVar contains an entry for this variant (Variation ID: 1048261). 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.

#	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 Institute of Human Genetics, University of Leipzig Medical Center, SCV004242439.2

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

Description

Criteria applied: PM3_STR,PM2_SUP,PP3; Identified as compund heterozygous with NM_000512.5:c.938C>T

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

Last Updated: Apr 13, 2025

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