NM_000404.4(GLB1):c.1769G>A (p.Arg590His) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Oct 23, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000794211.3

Allele description [Variation Report for NM_000404.4(GLB1):c.1769G>A (p.Arg590His)]

NM_000404.4(GLB1):c.1769G>A (p.Arg590His)

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.1769G>A (p.Arg590His)
HGVS:
  • NC_000003.12:g.32997310C>T
  • NG_009005.1:g.104893G>A
  • NM_000404.4:c.1769G>AMANE SELECT
  • NM_001079811.3:c.1679G>A
  • NM_001135602.3:c.1376G>A
  • NM_001317040.2:c.1913G>A
  • NM_001393580.1:c.1734+16746G>A
  • NP_000395.2:p.Arg590His
  • NP_000395.2:p.Arg590His
  • NP_000395.3:p.Arg590His
  • NP_001073279.2:p.Arg560His
  • NP_001129074.2:p.Arg459His
  • NP_001303969.2:p.Arg638His
  • NC_000003.11:g.33038802C>T
  • NM_000404.2:c.1769G>A
Protein change:
R459H
Links:
dbSNP: rs398123351
NCBI 1000 Genomes Browser:
rs398123351
Molecular consequence:
  • NM_001393580.1:c.1734+16746G>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000404.4:c.1769G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079811.3:c.1679G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001135602.3:c.1376G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317040.2:c.1913G>A - 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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000933605Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 23, 2020)
germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

MRI/MRS as a surrogate marker for clinical progression in GM1 gangliosidosis.

Regier DS, Kwon HJ, Johnston J, Golas G, Yang S, Wiggs E, Latour Y, Thomas S, Portner C, Adams D, Vezina G, Baker EH, Tifft CJ.

Am J Med Genet A. 2016 Mar;170(3):634-44. doi: 10.1002/ajmg.a.37468. Epub 2015 Dec 8.

PubMed [citation]
PMID:
26646981

Mutations in acid beta-galactosidase cause GM1-gangliosidosis in American patients.

Boustany RM, Qian WH, Suzuki K.

Am J Hum Genet. 1993 Oct;53(4):881-8.

PubMed [citation]
PMID:
8213816
PMCID:
PMC1682392
See all PubMed Citations (8)

Details of each submission

From Invitae, SCV000933605.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces arginine with histidine at codon 590 of the GLB1 protein (p.Arg590His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs398123351, ExAC 0.002%). This variant has been observed in individuals affected with GM1-gangliosidosis (PMID: 8213816, 26646981). ClinVar contains an entry for this variant (Variation ID: 92901). Experimental studies have shown that this missense change disrupts β-galactosidase activity (PMID: 8213816, 23337983). Variants that disrupt the p.Arg590 amino acid residue in GLB1 have been observed in affected individuals (PMID: 16941474, 23430803, 17309651, 17664528). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 20, 2021

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