NM_000512.5(GALNS):c.647T>C (p.Phe216Ser) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Sep 27, 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:: RCV001578571.15

Allele description [Variation Report for NM_000512.5(GALNS):c.647T>C (p.Phe216Ser)]

NM_000512.5(GALNS):c.647T>C (p.Phe216Ser)

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.647T>C (p.Phe216Ser)

Other names:

p.Phe216Ser

HGVS:

NC_000016.10:g.88835836A>G
NG_008667.1:g.26131T>C
NM_000512.5:c.647T>CMANE SELECT
NM_001323543.2:c.92T>C
NM_001323544.2:c.665T>C
NP_000503.1:p.Phe216Ser
NP_001310472.1:p.Phe31Ser
NP_001310473.1:p.Phe222Ser
NC_000016.9:g.88902244A>G

Protein change:

F216S

Links:

dbSNP: rs747805226

NCBI 1000 Genomes Browser:

rs747805226

Molecular consequence:

NM_000512.5:c.647T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.92T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.665T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Unknown function

Observations:

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
SCV001547761	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 24726177, 25252036, 31200731, 34387910, 25741868
SCV001960902	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Sep 20, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045016	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]
SCV002234455	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24726177, 25252036, 28492532
SCV005073881	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]

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	clinical testing, 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
Hindu	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinical, biochemical and genetic profiles of patients with mucopolysaccharidosis type IVA (Morquio A syndrome) in Malaysia: the first national natural history cohort study.

Leong HY, Abdul Azize NA, Chew HB, Keng WT, Thong MK, Mohd Khalid MKN, Hung LC, Mohamed Zainudin N, Ramlee A, Md Haniffa MA, Yakob Y, Ngu LH.

Orphanet J Rare Dis. 2019 Jun 14;14(1):143. doi: 10.1186/s13023-019-1105-6.

PubMed [citation]

PMID:: 31200731
PMCID:: PMC6570902

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 (6)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547761.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

In vivo functional studies supportive of a damaging effect on the gene product (low to null enzymatic activity in homozygotes; PS3_strong); 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 Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV001960902.1

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

Description

A heterozygous missense variation in exon 7 of the GALNS gene that results in the amino acid substitution of Serine for Phenylalanine at codon216 was detected. The observed variant c.647T>C (p.Phe216Ser) has not been reported in 1000 genomes and has a minor allele frequency of 0.0007% in the gnomAD databases. The in silico prediction of the variant is disease causing by DANN, SIFT and MutationTaster. The variant is in trans to a known pathogenic variant in the GALNS gene. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a likely pathogenic variant.

#	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 Genome-Nilou Lab, SCV002045016.1

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002234455.4

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

Description

This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 216 of the GALNS protein (p.Phe216Ser). This variant is present in population databases (rs747805226, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 24726177, 25252036). ClinVar contains an entry for this variant (Variation ID: 1048469). 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. 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

From Neuberg Centre For Genomic Medicine, NCGM, SCV005073881.2

#	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 c.647T>C (p.Phe216Ser) in GALNS gene has been reported previously in homozygous and compound heterozygous states in multiple individuals with mucopolysaccharidosis IVA (Bidchol et al., 2014, Leong et al., 2019; Morrone et al., 2014). Experimental studies support a damaging effect on the gene product (low to null enzymatic activity) (Morrone et al., 2014). It is one of the most common mutation in Indian population (Bidchol et al., 2014). This variant is present with an allele frequency of 0.0008% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely pathogenic / Pathogenic. Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict damaging effect on protein structure and function for this variant. The reference amino acid at this position in GALNS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Phe at position 216 is changed to a Ser changing protein sequence and it might alter its composition and physico-chemical properties. 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

Last Updated: Feb 25, 2025

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