NM_000404.4(GLB1):c.1038G>C (p.Lys346Asn) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Sep 26, 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:: RCV000821368.4

Allele description [Variation Report for NM_000404.4(GLB1):c.1038G>C (p.Lys346Asn)]

NM_000404.4(GLB1):c.1038G>C (p.Lys346Asn)

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.1038G>C (p.Lys346Asn)

HGVS:

NC_000003.12:g.33046150C>G
NG_009005.1:g.56053G>C
NM_000404.4:c.1038G>CMANE SELECT
NM_001079811.3:c.948G>C
NM_001135602.3:c.645G>C
NM_001317040.2:c.1182G>C
NM_001393580.1:c.1038G>C
NP_000395.3:p.Lys346Asn
NP_001073279.2:p.Lys316Asn
NP_001129074.2:p.Lys215Asn
NP_001303969.2:p.Lys394Asn
NP_001380509.1:p.Lys346Asn
NC_000003.11:g.33087642C>G
NM_000404.2:c.1038G>C

Protein change:

K215N

Links:

dbSNP: rs749980306

NCBI 1000 Genomes Browser:

rs749980306

Molecular consequence:

NM_000404.4:c.1038G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.948G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.645G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.1182G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001393580.1:c.1038G>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
SCV000962123	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 26, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 16941474, 19472408, 24777551, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000962123

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Sep 26, 2023)

germline

clinical testing

PubMed (4)
[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

Twenty-one novel mutations in the GLB1 gene identified in a large group of GM1-gangliosidosis and Morquio B patients: possible common origin for the prevalent p.R59H mutation among gypsies.

Santamaria R, Chabás A, Coll MJ, Miranda CS, Vilageliu L, Grinberg D.

Hum Mutat. 2006 Oct;27(10):1060.

PubMed [citation]

PMID:: 16941474

GM1 gangliosidosis and Morquio B disease: expression analysis of missense mutations affecting the catalytic site of acid beta-galactosidase.

Hofer D, Paul K, Fantur K, Beck M, Bürger F, Caillaud C, Fumic K, Ledvinova J, Lugowska A, Michelakakis H, Radeva B, Ramaswami U, Plecko B, Paschke E.

Hum Mutat. 2009 Aug;30(8):1214-21. doi: 10.1002/humu.21031.

PubMed [citation]

PMID:: 19472408

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000962123.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 346 of the GLB1 protein (p.Lys346Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with GM1-gangliosidosis (PMID: 16941474, 19472408, 24777551). ClinVar contains an entry for this variant (Variation ID: 550856). 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. 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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