NM_000404.4(GLB1):c.245C>T (p.Thr82Met) 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:: RCV001068811.4

Allele description [Variation Report for NM_000404.4(GLB1):c.245C>T (p.Thr82Met)]

NM_000404.4(GLB1):c.245C>T (p.Thr82Met)

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.245C>T (p.Thr82Met)

HGVS:

NC_000003.12:g.33072544G>A
NG_009005.1:g.29659C>T
NM_000404.4:c.245C>TMANE SELECT
NM_001079811.3:c.155C>T
NM_001135602.3:c.245C>T
NM_001317040.2:c.389C>T
NM_001393580.1:c.245C>T
NP_000395.3:p.Thr82Met
NP_001073279.2:p.Thr52Met
NP_001129074.2:p.Thr82Ile
NP_001303969.2:p.Thr130Met
NP_001380509.1:p.Thr82Met
NC_000003.11:g.33114036G>A
NM_000404.2:c.245C>T
NM_000404.3:c.245C>T

Protein change:

T130M; THR82MET

Links:

OMIM: 611458.0013; dbSNP: rs72555393

NCBI 1000 Genomes Browser:

rs72555393

Molecular consequence:

NM_000404.4:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.155C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.245C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.389C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001393580.1:c.245C>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
SCV001233943	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, 20175788, 21520340, 25326637, 8198123, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001233943

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

Phenotype determining alleles in GM1 gangliosidosis patients bearing novel GLB1 mutations.

Hofer D, Paul K, Fantur K, Beck M, Roubergue A, Vellodi A, Poorthuis BJ, Michelakakis H, Plecko B, Paschke E.

Clin Genet. 2010 Sep;78(3):236-46. doi: 10.1111/j.1399-0004.2010.01379.x. Epub 2010 Feb 11.

PubMed [citation]

PMID:: 20175788

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001233943.4

#	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 threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 82 of the GLB1 protein (p.Thr82Met). This variant is present in population databases (rs72555393, gnomAD 0.009%). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 8198123, 11511921, 20175788, 21520340, 25326637). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 8198123). 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: May 19, 2024

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