NM_000512.5(GALNS):c.938C>T (p.Thr313Met) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (7 submissions)
Last evaluated:: Jul 10, 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:: RCV001578324.15

Allele description [Variation Report for NM_000512.5(GALNS):c.938C>T (p.Thr313Met)]

NM_000512.5(GALNS):c.938C>T (p.Thr313Met)

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.938C>T (p.Thr313Met)

Other names:

p.Thr313Met

HGVS:

NC_000016.10:g.88832062G>A
NG_008667.1:g.29905C>T
NM_000512.5:c.938C>TMANE SELECT
NM_001323543.2:c.383C>T
NM_001323544.2:c.956C>T
NP_000503.1:p.Thr313Met
NP_001310472.1:p.Thr128Met
NP_001310473.1:p.Thr319Met
NC_000016.9:g.88898470G>A
NM_000512.4:c.938C>T
NM_001323544.2:c.956C>T

Protein change:

T128M

Links:

dbSNP: rs894525161

NCBI 1000 Genomes Browser:

rs894525161

Molecular consequence:

NM_000512.5:c.938C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.383C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.956C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001547848	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 (6) [See all records that cite these PMIDs] 23876334, 25252036, 28397226, 32993725, 34387910, 25741868
SCV002025252	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Oct 4, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003443643	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 21, 2022)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23876334, 25252036, 32993725, 28492532
SCV003915845	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004100660	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004242438	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]
SCV005200347	Dr.Nikuei Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 10, 2024)	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	1	not provided	not provided	not provided	not provided	clinical testing, 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

[Analysis of clinical features and GALNS gene mutation in a patient with mucopolysaccharidosis type IV A].

Chen Q, Chen Y, Liu X, Wei H.

Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2017 Apr 10;34(2):232-235. doi: 10.3760/cma.j.issn.1003-9406.2017.02.018. Chinese.

PubMed [citation]

PMID:: 28397226

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, SCV001547848.3

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

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 Revvity Omics, Revvity, SCV002025252.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003443643.2

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

Description

This missense change has been observed in individual(s) with Morquio syndrome type A (PMID: 23876334, 25252036, 32993725). This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 313 of the GALNS protein (p.Thr313Met). ClinVar contains an entry for this variant (Variation ID: 1048222). For these reasons, this variant has been classified as Pathogenic. 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.

#	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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV003915845.1

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

Description

A Heterozygous missense variation in exon 9 of the GALNS gene that results in the amino acid substitution of Methionine for Threonine at codon 313 was detected. The observed variant c.938C>T (p.Thr313Met) has not been reported in the 1000 genomes and has a MAF of 0.0016% in gnomAD databases. The in silico prediction of the variant is disease causing by MutationTaster. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic.

#	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		1	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004100660.2

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

Description

The missense variant p.T313M in GALNS (NM_000512.5) has been reported previously in multiple affected individuals (PMID: 23876334, 25252036, 32993725) The p.T313M variant is observed in 2/34,528 (0.0058%) alleles from individuals of Latino background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes.The p.T313M missense variant is predicted to be damaging by both SIFT and PolyPhen2. The threonine residue at codon 313 of GALNS is conserved in all mammalian species. The nucleotide c.938 in GALNS is predicted conserved by GERP++ and PhyloP across 100 vertebrates. 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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, University of Leipzig Medical Center, SCV004242438.1

#	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.143T>G

#	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

From Dr.Nikuei Genetic Center, SCV005200347.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

Relating variation to medicine