NM_000512.5(GALNS):c.289T>G (p.Phe97Val) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Dec 31, 2022
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:: RCV001578283.7

Allele description [Variation Report for NM_000512.5(GALNS):c.289T>G (p.Phe97Val)]

NM_000512.5(GALNS):c.289T>G (p.Phe97Val)

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.289T>G (p.Phe97Val)

HGVS:

NC_000016.10:g.88841927A>C
NG_008667.1:g.20040T>G
NM_000512.5:c.289T>GMANE SELECT
NM_001323543.2:c.-267T>G
NM_001323544.2:c.307T>G
NP_000503.1:p.Phe97Val
NP_001310473.1:p.Phe103Val
NC_000016.9:g.88908335A>C

Protein change:

F103V

Links:

dbSNP: rs2143005083

NCBI 1000 Genomes Browser:

rs2143005083

Molecular consequence:

NM_001323543.2:c.-267T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000512.5:c.289T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.307T>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
SCV001547651	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 (4) [See all records that cite these PMIDs] 16287098, 8826435, 34387910, 25741868
SCV004296421	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 31, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 9375852, 10814710, 8826435, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547651

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

SCV004296421

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 31, 2022)

germline

clinical testing

PubMed (4)
[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

Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A).

Tomatsu S, Montaño AM, Nishioka T, Gutierrez MA, Peña OM, Tranda Firescu GG, Lopez P, Yamaguchi S, Noguchi A, Orii T.

Hum Mutat. 2005 Dec;26(6):500-12.

PubMed [citation]

PMID:: 16287098

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

See all PubMed Citations (7)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547651.3

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

Description

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, SCV004296421.2

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects GALNS function (PMID: 8826435, 9375852, 10814710). 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: 1048180). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 8826435). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 97 of the GALNS protein (p.Phe97Val).

#	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: Mar 5, 2025

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