NM_000512.5(GALNS):c.1169T>C (p.Leu390Pro) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: May 19, 2023
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:: RCV001578337.7

Allele description [Variation Report for NM_000512.5(GALNS):c.1169T>C (p.Leu390Pro)]

NM_000512.5(GALNS):c.1169T>C (p.Leu390Pro)

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.1169T>C (p.Leu390Pro)

HGVS:

NC_000016.10:g.88824840A>G
NG_008667.1:g.37127T>C
NM_000512.5:c.1169T>CMANE SELECT
NM_001323543.2:c.614T>C
NM_001323544.2:c.1187T>C
NP_000503.1:p.Leu390Pro
NP_001310472.1:p.Leu205Pro
NP_001310473.1:p.Leu396Pro
NC_000016.9:g.88891248A>G

Protein change:

L205P

Links:

dbSNP: rs2142993863

NCBI 1000 Genomes Browser:

rs2142993863

Molecular consequence:

NM_000512.5:c.1169T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.614T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.1187T>C - 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
SCV001547912	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 (3) [See all records that cite these PMIDs] 24120057, 34387910, 25741868
SCV004297059	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 19, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 24120057, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547912

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

SCV004297059

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 19, 2023)

germline

clinical testing

PubMed (2)
[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 (4)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547912.3

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

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, SCV004297059.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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: 1048235). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24120057). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 390 of the GALNS protein (p.Leu390Pro). 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

Last Updated: Mar 5, 2025

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