NM_000404.4(GLB1):c.841C>T (p.His281Tyr) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 11, 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:: RCV000805468.5

Allele description [Variation Report for NM_000404.4(GLB1):c.841C>T (p.His281Tyr)]

NM_000404.4(GLB1):c.841C>T (p.His281Tyr)

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.841C>T (p.His281Tyr)

HGVS:

NC_000003.12:g.33051956G>A
NG_009005.1:g.50247C>T
NM_000404.4:c.841C>TMANE SELECT
NM_001079811.3:c.751C>T
NM_001135602.3:c.448C>T
NM_001317040.2:c.985C>T
NM_001393580.1:c.841C>T
NP_000395.3:p.His281Tyr
NP_001073279.2:p.His251Tyr
NP_001129074.2:p.His150Tyr
NP_001303969.1:p.His329Tyr
NP_001303969.2:p.His329Tyr
NP_001380509.1:p.His281Tyr
NC_000003.11:g.33093448G>A
NM_000404.2:c.841C>T
NM_001317040.1:c.985C>T

Protein change:

H150Y

Links:

dbSNP: rs745386663

NCBI 1000 Genomes Browser:

rs745386663

Molecular consequence:

NM_000404.4:c.841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.751C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.448C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.985C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001393580.1:c.841C>T - 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
SCV000945425	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 11, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11511921, 15714521, 18546276, 21214877, 21497194, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000945425

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 11, 2024)

germline

clinical testing

PubMed (6)
[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

Mutation analyses in 17 patients with deficiency in acid beta-galactosidase: three novel point mutations and high correlation of mutation W273L with Morquio disease type B.

Paschke E, Milos I, Kreimer-Erlacher H, Hoefler G, Beck M, Hoeltzenbein M, Kleijer W, Levade T, Michelakakis H, Radeva B.

Hum Genet. 2001 Aug;109(2):159-66.

PubMed [citation]

PMID:: 11511921

Role of beta-galactosidase and elastin binding protein in lysosomal and nonlysosomal complexes of patients with GM1-gangliosidosis.

Caciotti A, Donati MA, Boneh A, d'Azzo A, Federico A, Parini R, Antuzzi D, Bardelli T, Nosi D, Kimonis V, Zammarchi E, Morrone A.

Hum Mutat. 2005 Mar;25(3):285-92.

PubMed [citation]

PMID:: 15714521

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000945425.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 281 of the GLB1 protein (p.His281Tyr). This variant is present in population databases (rs745386663, gnomAD 0.003%). This missense change has been observed in individual(s) with GLB1-related conditions (PMID: 11511921, 15714521, 18546276, 21214877, 21497194). 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: 372371). 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: Mar 5, 2024

ClinVar

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