NM_000404.4(GLB1):c.1771T>C (p.Tyr591His) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 6, 2022
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:: RCV003079045.2

Allele description [Variation Report for NM_000404.4(GLB1):c.1771T>C (p.Tyr591His)]

NM_000404.4(GLB1):c.1771T>C (p.Tyr591His)

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.1771T>C (p.Tyr591His)

HGVS:

NC_000003.12:g.32997308A>G
NG_009005.2:g.104838T>C
NM_000404.4:c.1771T>CMANE SELECT
NM_001079811.3:c.1681T>C
NM_001135602.3:c.1378T>C
NM_001317040.2:c.1915T>C
NM_001393580.1:c.1734+16748T>C
NP_000395.3:p.Tyr591His
NP_001073279.2:p.Tyr561His
NP_001129074.2:p.Tyr460His
NP_001303969.2:p.Tyr639His
NC_000003.11:g.33038800A>G
NG_009005.1:g.104895T>C

Protein change:

Y460H

Molecular consequence:

NM_001393580.1:c.1734+16748T>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000404.4:c.1771T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.1681T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.1378T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.1915T>C - 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
SCV003459859	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 6, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 10737981, 29439846, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003459859

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 6, 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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

beta-galactosidase gene mutations affecting the lysosomal enzyme and the elastin-binding protein in GM1-gangliosidosis patients with cardiac involvement.

Morrone A, Bardelli T, Donati MA, Giorgi M, Di Rocco M, Gatti R, Parini R, Ricci R, Taddeucci G, D'Azzo A, Zammarchi E.

Hum Mutat. 2000;15(4):354-66.

PubMed [citation]

PMID:: 10737981

Diagnostic challenge for the rare lysosomal storage disease: Late infantile GM1 gangliosidosis.

Lee JS, Choi JM, Lee M, Kim SY, Lee S, Lim BC, Cheon JE, Kim IO, Kim KJ, Choi M, Seong MW, Chae JH.

Brain Dev. 2018 May;40(5):383-390. doi: 10.1016/j.braindev.2018.01.009. Epub 2018 Feb 10.

PubMed [citation]

PMID:: 29439846

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV003459859.2

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

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Tyr591 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10737981). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 29439846). This variant is present in population databases (rs72555373, gnomAD 0.002%). This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 591 of the GLB1 protein (p.Tyr591His).

#	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: Feb 28, 2024

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