NM_000404.4(GLB1):c.1498A>G (p.Thr500Ala) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 8, 2024
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001040694.6

Allele description [Variation Report for NM_000404.4(GLB1):c.1498A>G (p.Thr500Ala)]

NM_000404.4(GLB1):c.1498A>G (p.Thr500Ala)

Gene:

GLB1:galactosidase beta 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p22.3

Genomic location:

Preferred name:

NM_000404.4(GLB1):c.1498A>G (p.Thr500Ala)

HGVS:

NC_000003.12:g.33014292T>C
NG_009005.1:g.87911A>G
NM_000404.4:c.1498A>GMANE SELECT
NM_001079811.3:c.1408A>G
NM_001135602.3:c.1105A>G
NM_001317040.2:c.1642A>G
NM_001393580.1:c.1498A>G
NP_000395.3:p.Thr500Ala
NP_001073279.2:p.Thr470Ala
NP_001129074.2:p.Thr369Ala
NP_001303969.2:p.Thr548Ala
NP_001380509.1:p.Thr500Ala
NC_000003.11:g.33055784T>C
NM_000404.2:c.1498A>G
NM_000404.3:c.1498A>G

Protein change:

T369A; THR500ALA

Links:

OMIM: 611458.0020; dbSNP: rs72555368

NCBI 1000 Genomes Browser:

rs72555368

Molecular consequence:

NM_000404.4:c.1498A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.1408A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.1105A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.1642A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001393580.1:c.1498A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Mucopolysaccharidosis, MPS-IV-B (MPS4B)
Synonyms:: MPS IVB; Morquio syndrome B; MPS 4B; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009660; MedGen: C0086652; Orphanet: 582; OMIM: 253010

Name:: GM1 gangliosidosis
Synonyms:: Beta galactosidase 1 deficiency; GLB 1 deficiency
Identifiers:: MONDO: MONDO:0018149; MedGen: C0085131

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001204283	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 8, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12393180, 17664528, 19472408, 26108645, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001204283

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 8, 2024)

germline

clinical testing

PubMed (5)
[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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Novel mutations (Asn 484 Lys, Thr 500 Ala, Gly 438 Glu) in Morquio B disease.

Bagshaw RD, Zhang S, Hinek A, Skomorowski MA, Whelan D, Clarke JT, Callahan JW.

Biochim Biophys Acta. 2002 Dec 12;1588(3):247-53.

PubMed [citation]

PMID:: 12393180

Expression and characterization of 14 GLB1 mutant alleles found in GM1-gangliosidosis and Morquio B patients.

Santamaria R, Chabás A, Callahan JW, Grinberg D, Vilageliu L.

J Lipid Res. 2007 Oct;48(10):2275-82. Epub 2007 Jul 30.

PubMed [citation]

PMID:: 17664528

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001204283.4

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 500 of the GLB1 protein (p.Thr500Ala). This variant is present in population databases (rs72555368, gnomAD 0.003%). This missense change has been observed in individual(s) with Morquio B disease or GM1 gangliosidosis (PMID: 12393180, 17664528, 19472408, 26108645). ClinVar contains an entry for this variant (Variation ID: 942). 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 GLB1 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

Last Updated: Sep 29, 2024

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