NM_000512.5(GALNS):c.860C>T (p.Ser287Leu) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic (9 submissions)
Last evaluated:: Mar 14, 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:: RCV000701162.24

Allele description [Variation Report for NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)]

NM_000512.5(GALNS):c.860C>T (p.Ser287Leu)

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.860C>T (p.Ser287Leu)

HGVS:

NC_000016.10:g.88835251G>A
NG_008667.1:g.26716C>T
NM_000512.5:c.860C>TMANE SELECT
NM_001323543.2:c.305C>T
NM_001323544.2:c.878C>T
NP_000503.1:p.Ser287Leu
NP_001310472.1:p.Ser102Leu
NP_001310473.1:p.Ser293Leu
NC_000016.9:g.88901659G>A
NM_000512.4:c.860C>T
P34059:p.Ser287Leu

Protein change:

S102L

Links:

UniProtKB: P34059#VAR_007211; dbSNP: rs770053354

NCBI 1000 Genomes Browser:

rs770053354

Molecular consequence:

NM_000512.5:c.860C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.305C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.878C>T - 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
SCV000829946	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 9298823, 15235041, 16287098, 23876334, 25252036, 29731656, 28492532
SCV001190762	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	no assertion criteria provided	Pathogenic (Feb 5, 2020)	germline	clinical testing
SCV001366701	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 14, 2018)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001547809	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	research	PubMed (13) [See all records that cite these PMIDs] 15235041, 16287098, 22521955, 23876334, 24726177, 25252036, 25545067, 26147980, 29731656, 30980944, 9298823, 34387910, 25741868
SCV002024156	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 10, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002045010	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Nov 7, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002792927	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 18, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004801250	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 14, 2024)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV005061243	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	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	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, research
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mucopolysaccharidosis IVA: identification of mutations and methylation study in GALNS gene.

Tomatsu S, Nishioka T, Montaño AM, Gutierrez MA, Pena OS, Orii KO, Sly WS, Yamaguchi S, Orii T, Paschke E, Kircher SG, Noguchi A.

J Med Genet. 2004 Jul;41(7):e98. No abstract available.

PubMed [citation]

PMID:: 15235041
PMCID:: PMC1735846

See all PubMed Citations (14)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000829946.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 287 of the GALNS protein (p.Ser287Leu). This variant is present in population databases (rs770053354, gnomAD 0.003%). This missense change has been observed in individual(s) with mucopolysaccharidosis IV type A (PMID: 9298823, 15235041, 16287098, 23876334, 25252036, 29731656). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 265169). 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 with a positive predictive value of 95%. 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 Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City, SCV001190762.1

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

#	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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001366701.2

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

Description

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP2,PP3.

#	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 Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547809.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (13)

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 Revvity Omics, Revvity, SCV002024156.3

#	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 Genome-Nilou Lab, SCV002045010.1

#	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 Fulgent Genetics, Fulgent Genetics, SCV002792927.1

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

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV004801250.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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 Neuberg Centre For Genomic Medicine, NCGM, SCV005061243.1

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

Description

The missense c.860C>T (p.Ser287Leu) variant in the GALNS gene has been observed in individual(s) with mucopolysaccharidosis IV type A (Tomatsu, Shunji et al., 2005). Mapping of the p.Ser287Leu variant to the X-ray crystallography structure of the GALNS protein found that this variant is buried within the protein and likely results in loss of proper hydrogen bonding (Rivera-Colon et al., 2012). This variant is reported with the allele frequency (0.001%) in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). The amino acid Serine at position 287 is changed to a Leucine changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted as damaging by SIFT. The amino acid change p.Ser287Leu in GALNS is predicted as 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

Last Updated: Oct 8, 2024

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