NM_000404.4(GLB1):c.971A>G (p.Tyr324Cys) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 8, 2023
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:: RCV003767999.1

Allele description [Variation Report for NM_000404.4(GLB1):c.971A>G (p.Tyr324Cys)]

NM_000404.4(GLB1):c.971A>G (p.Tyr324Cys)

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.971A>G (p.Tyr324Cys)

HGVS:

NC_000003.12:g.33046217T>C
NG_009005.1:g.55986A>G
NM_000404.4:c.971A>GMANE SELECT
NM_001079811.3:c.881A>G
NM_001135602.3:c.578A>G
NM_001317040.2:c.1115A>G
NM_001393580.1:c.971A>G
NP_000395.3:p.Tyr324Cys
NP_001073279.2:p.Tyr294Cys
NP_001129074.2:p.Tyr193Cys
NP_001303969.2:p.Tyr372Cys
NP_001380509.1:p.Tyr324Cys
NC_000003.11:g.33087709T>C
NM_000404.2:c.971A>G

Protein change:

Y193C

Links:

dbSNP: rs977975596

NCBI 1000 Genomes Browser:

rs977975596

Molecular consequence:

NM_000404.4:c.971A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.881A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.578A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.1115A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001393580.1:c.971A>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
SCV004569528	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Sep 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23337983, 16617000, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004569528

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Sep 8, 2023)

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

A bicyclic 1-deoxygalactonojirimycin derivative as a novel pharmacological chaperone for GM1 gangliosidosis.

Takai T, Higaki K, Aguilar-Moncayo M, Mena-Barragán T, Hirano Y, Yura K, Yu L, Ninomiya H, García-Moreno MI, Sakakibara Y, Ohno K, Nanba E, Ortiz Mellet C, García Fernández JM, Suzuki Y.

Mol Ther. 2013 Mar;21(3):526-32. doi: 10.1038/mt.2012.263. Epub 2013 Jan 22.

PubMed [citation]

PMID:: 23337983
PMCID:: PMC3589148

Fibroblast screening for chaperone therapy in beta-galactosidosis.

Iwasaki H, Watanabe H, Iida M, Ogawa S, Tabe M, Higaki K, Nanba E, Suzuki Y.

Brain Dev. 2006 Sep;28(8):482-6. Epub 2006 Apr 17.

PubMed [citation]

PMID:: 16617000

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004569528.1

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

Description

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. Experimental studies have shown that this missense change affects GLB1 function (PMID: 23337983). 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. ClinVar contains an entry for this variant (Variation ID: 556658). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 324 of the GLB1 protein (p.Tyr324Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of GLB1-related conditions (PMID: 16617000; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant.

#	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

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