NM_000512.5(GALNS):c.866A>G (p.Asn289Ser) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: May 19, 2023
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:: RCV001578528.5

Allele description [Variation Report for NM_000512.5(GALNS):c.866A>G (p.Asn289Ser)]

NM_000512.5(GALNS):c.866A>G (p.Asn289Ser)

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.866A>G (p.Asn289Ser)

HGVS:

NC_000016.10:g.88835245T>C
NG_008667.1:g.26722A>G
NM_000512.5:c.866A>GMANE SELECT
NM_001323543.2:c.311A>G
NM_001323544.2:c.884A>G
NP_000503.1:p.Asn289Ser
NP_001310472.1:p.Asn104Ser
NP_001310473.1:p.Asn295Ser
NC_000016.9:g.88901653T>C

Protein change:

N104S

Links:

dbSNP: rs1465096387

NCBI 1000 Genomes Browser:

rs1465096387

Molecular consequence:

NM_000512.5:c.866A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.311A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.884A>G - 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
SCV001547813	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Feb 1, 2021)	germline	curation	PubMed (3) [See all records that cite these PMIDs] 20574428, 34387910, 25741868
SCV004297068	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 19, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24726177, 20574428, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547813

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

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Feb 1, 2021)

germline

curation

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

SCV004297068

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 19, 2023)

germline

clinical testing

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

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants.

Zanetti A, D'Avanzo F, AlSayed M, Brusius-Facchin AC, Chien YH, Giugliani R, Izzo E, Kasper DC, Lin HY, Lin SP, Pollard L, Singh A, Tonin R, Wood T, Morrone A, Tomanin R.

Hum Mutat. 2021 Nov;42(11):1384-1398. doi: 10.1002/humu.24270. Epub 2021 Aug 23. Review.

PubMed [citation]

PMID:: 34387910
PMCID:: PMC9291100

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

See all PubMed Citations (5)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547813.3

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

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); located in a mutational hot spot and/or critical and well-established functional domain without benign variation (PM1_moderate); 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 Labcorp Genetics (formerly Invitae), Labcorp, SCV004297068.1

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

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asn289 amino acid residue in GALNS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24726177). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 1048426). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 20574428). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 289 of the GALNS protein (p.Asn289Ser).

#	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: Sep 29, 2024

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