NM_000512.5(GALNS):c.77dup (p.Ala27fs) AND Mucopolysaccharidosis, MPS-IV-A

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Nov 23, 2022
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:: RCV001578352.5

Allele description [Variation Report for NM_000512.5(GALNS):c.77dup (p.Ala27fs)]

NM_000512.5(GALNS):c.77dup (p.Ala27fs)

Genes:

LOC130059762:ATAC-STARR-seq lymphoblastoid silent region 7883 [Gene]
GALNS:galactosamine (N-acetyl)-6-sulfatase [Gene - OMIM - HGNC]
TRAPPC2L:trafficking protein particle complex subunit 2L [Gene - OMIM - HGNC]

Variant type:

Duplication

Cytogenetic location:

16q24.3

Genomic location:

Preferred name:

NM_000512.5(GALNS):c.77dup (p.Ala27fs)

HGVS:

NC_000016.10:g.88856803dup
NG_008667.1:g.5166dup
NM_000512.5:c.77dupMANE SELECT
NM_001323543.2:c.-355dup
NM_001323544.2:c.-76dup
NP_000503.1:p.Ala27fs
NC_000016.9:g.88923208_88923209insC
NC_000016.9:g.88923211dup

Protein change:

A27fs

Links:

dbSNP: rs2143013573

NCBI 1000 Genomes Browser:

rs2143013573

Molecular consequence:

NM_001323543.2:c.-355dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001323544.2:c.-76dup - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000512.5:c.77dup - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV001547575	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 (2) [See all records that cite these PMIDs] 34387910, 25741868
SCV004660488	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 23, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 34387910, 12442278, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001547575

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 (2)
[See all records that cite these PMIDs]

SCV004660488

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 23, 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

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

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 (4)

Details of each submission

From Laboratory of Diagnosis and Therapy of Lysosomal Disorders, University of Padova, SCV001547575.3

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

Description

Frameshift variant (PVS1_very strong); absent from gnomAD v2.1.1 (PM2_moderate)

#	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, SCV004660488.1

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

Description

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1048252). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IVA (PMID: 34387910). This sequence change creates a premature translational stop signal (p.Ala27Argfs*19) in the GALNS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALNS are known to be pathogenic (PMID: 12442278).

#	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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