NM_000404.4(GLB1):c.1742T>G (p.Val581Gly) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 2, 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:: RCV003802311.1

Allele description [Variation Report for NM_000404.4(GLB1):c.1742T>G (p.Val581Gly)]

NM_000404.4(GLB1):c.1742T>G (p.Val581Gly)

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.1742T>G (p.Val581Gly)

HGVS:

NC_000003.12:g.32997337A>C
NG_009005.1:g.104866T>G
NG_009005.2:g.104809T>G
NG_099014.1:g.1A>C
NM_000404.4:c.1742T>GMANE SELECT
NM_001079811.3:c.1652T>G
NM_001135602.3:c.1349T>G
NM_001317040.2:c.1886T>G
NM_001393580.1:c.1734+16719T>G
NP_000395.3:p.Val581Gly
NP_001073279.2:p.Val551Gly
NP_001129074.2:p.Val450Gly
NP_001303969.2:p.Val629Gly
NC_000003.11:g.33038829A>C

Protein change:

V450G

Molecular consequence:

NM_001393580.1:c.1734+16719T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000404.4:c.1742T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001079811.3:c.1652T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001135602.3:c.1349T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001317040.2:c.1886T>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

Recent activity

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PREDICTED: Homo sapiens solute carrier family 39 member 13 (SLC39A13), transcrip...
PREDICTED: Homo sapiens solute carrier family 39 member 13 (SLC39A13), transcript variant X6, mRNA
gi|1370460597|ref|XM_017018540.2|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004608903	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004608903

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 2, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV004608903.1

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

Description

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 581 of the GLB1 protein (p.Val581Gly). 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 (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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%. 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.

#	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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