NM_000512.5(GALNS):c.824T>C (p.Leu275Pro) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: May 27, 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:: RCV001578522.10

Allele description [Variation Report for NM_000512.5(GALNS):c.824T>C (p.Leu275Pro)]

NM_000512.5(GALNS):c.824T>C (p.Leu275Pro)

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.824T>C (p.Leu275Pro)

HGVS:

NC_000016.10:g.88835287A>G
NG_008667.1:g.26680T>C
NM_000512.5:c.824T>CMANE SELECT
NM_001323543.2:c.269T>C
NM_001323544.2:c.842T>C
NP_000503.1:p.Leu275Pro
NP_001310472.1:p.Leu90Pro
NP_001310473.1:p.Leu281Pro
NC_000016.9:g.88901695A>G

Protein change:

L275P

Links:

dbSNP: rs2143001162

NCBI 1000 Genomes Browser:

rs2143001162

Molecular consequence:

NM_000512.5:c.824T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323543.2:c.269T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001323544.2:c.842T>C - 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

Recent activity

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IL3-CT0219-280100-062-G01 CT0219 Homo sapiens cDNA, mRNA sequence
IL3-CT0219-280100-062-G01 CT0219 Homo sapiens cDNA, mRNA sequence
gi|7309056|gnl|dbEST|4037581|gb|AW6 .1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001547803	Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 1, 2021)	germline	research	PubMed (4) [See all records that cite these PMIDs] 25545067, 32216080, 34387910, 25741868
SCV002208089	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 27, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 32216080, 34387910, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547803

Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 1, 2021)

germline

research

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

SCV002208089

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 27, 2022)

germline

clinical testing

PubMed (3)
[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	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Optimizing the molecular diagnosis of GALNS: novel methods to define and characterize Morquio-A syndrome-associated mutations.

Caciotti A, Tonin R, Rigoldi M, Ferri L, Catarzi S, Cavicchi C, Procopio E, Donati MA, Ficcadenti A, Fiumara A, Barone R, Garavelli L, Rocco MD, Filocamo M, Antuzzi D, Scarpa M, Mooney SD, Li B, Skouma A, Bianca S, Concolino D, Casalone R, et al.

Hum Mutat. 2015 Mar;36(3):357-68. doi: 10.1002/humu.22751.

PubMed [citation]

PMID:: 25545067

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 (5)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547803.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	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, SCV002208089.3

#	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 leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 275 of the GALNS protein (p.Leu275Pro). 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. ClinVar contains an entry for this variant (Variation ID: 1048420). This missense change has been observed in individual(s) with mucopolysaccharidosis IVA (PMID: 32216080, 34387910). This variant is not present in population databases (gnomAD no frequency).

#	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: Sep 29, 2024

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