NM_000512.5(GALNS):c.421T>A (p.Trp141Arg) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 7, 2021
Review status:: criteria provided, conflicting classifications

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:: RCV000282371.14

Allele description [Variation Report for NM_000512.5(GALNS):c.421T>A (p.Trp141Arg)]

NM_000512.5(GALNS):c.421T>A (p.Trp141Arg)

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.421T>A (p.Trp141Arg)

HGVS:

NC_000016.10:g.88840993A>T
NG_008667.1:g.20974T>A
NM_000512.5:c.421T>AMANE SELECT
NM_001323543.2:c.-135T>A
NM_001323544.2:c.439T>A
NP_000503.1:p.Trp141Arg
NP_001310473.1:p.Trp147Arg
NC_000016.9:g.88907401A>T
NM_000512.4:c.421T>A
P34059:p.Trp141Arg

Protein change:

W141R

Links:

UniProtKB: P34059#VAR_007190; dbSNP: rs794727625

NCBI 1000 Genomes Browser:

rs794727625

Molecular consequence:

NM_001323543.2:c.-135T>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000512.5:c.421T>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.439T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-IV-A (MPS4A)
Synonyms:: MPS IVA; Morquio syndrome A; MPS 4A; 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
SCV000399654	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 09 May 2019)	Likely pathogenic (Apr 28, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22940367, 24411403, 9298823 Citation Link,
SCV001547683	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 24411403, 24726177, 30980944, 9298823, 34387910, 25741868
SCV002044963	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]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000399654

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 09 May 2019)

Likely pathogenic
(Apr 28, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link,

SCV001547683

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 1, 2021)

germline

curation

PubMed (6)
[See all records that cite these PMIDs]

SCV002044963

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]

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	curation
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The structure of human GALNS reveals the molecular basis for mucopolysaccharidosis IV A.

Rivera-Colón Y, Schutsky EK, Kita AZ, Garman SC.

J Mol Biol. 2012 Nov 9;423(5):736-51. doi: 10.1016/j.jmb.2012.08.020. Epub 2012 Aug 29.

PubMed [citation]

PMID:: 22940367
PMCID:: PMC3472114

Mutations and polymorphisms in N-acetylgalactosamine-6-sulfate sulfatase gene in Turkish Morquio A patients.

Khedhiri S, Chkioua L, Elcioglu N, Laradi S, Miled A.

Pathol Biol (Paris). 2014 Feb;62(1):38-40. doi: 10.1016/j.patbio.2013.10.001. Epub 2014 Jan 9.

PubMed [citation]

PMID:: 24411403

See all PubMed Citations (7)

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000399654.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

The GALNS c.421T>A (p.Trp141Arg) missense variant has been reported in two studies in which it was identified in a homozygous state in two patients with mucopolysaccharidosis type IV, both exhibiting a severe phenotype (Bunge et al. 1997; Khedhiri et al. 2014). The p.Trp141Arg variant was absent from the 116 control chromosomes and is not observed in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium in an area of good sequence coverage, suggesting it is rare. Negligible GALNS activity was observed in leukocytes extracted from one of the patients (Khedhiri et al. 2014). The Trp141 residue is well-conserved. Structural studies of the 3D structure of human GALNS demonstrated that the residue is located in the hydrophobic core of the enzyme near the active site (Rivera-ColÃ³n et al. 2012). Based on the available evidence, the p.Trp141Arg variant is classified as likely pathogenic for mucopolysaccharidosis type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.

#	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, SCV001547683.3

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

Description

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_supporting); the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4_supporting); absent from 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 Genome-Nilou Lab, SCV002044963.1

#	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

Last Updated: Jun 23, 2024

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