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NM_000404.4(GLB1):c.842A>G (p.His281Arg) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Aug 20, 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:
RCV002584751.4

Allele description [Variation Report for NM_000404.4(GLB1):c.842A>G (p.His281Arg)]

NM_000404.4(GLB1):c.842A>G (p.His281Arg)

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.842A>G (p.His281Arg)
HGVS:
  • NC_000003.12:g.33051955T>C
  • NG_009005.2:g.50191A>G
  • NM_000404.4:c.842A>GMANE SELECT
  • NM_001079811.3:c.752A>G
  • NM_001135602.3:c.449A>G
  • NM_001317040.2:c.986A>G
  • NM_001393580.1:c.842A>G
  • NP_000395.3:p.His281Arg
  • NP_001073279.2:p.His251Arg
  • NP_001129074.2:p.His150Arg
  • NP_001303969.2:p.His329Arg
  • NP_001380509.1:p.His281Arg
  • NC_000003.11:g.33093447T>C
  • NG_009005.1:g.50248A>G
Protein change:
H150R
Links:
dbSNP: rs1198846361
NCBI 1000 Genomes Browser:
rs1198846361
Molecular consequence:
  • NM_000404.4:c.842A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079811.3:c.752A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001135602.3:c.449A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317040.2:c.986A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001393580.1:c.842A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Mucopolysaccharidosis, MPS-IV-B (MPS4B)
Synonyms:
MORQUIO SYNDROME B; MPS IVB; Mucopolysaccharidosis type IV B; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0009660; MedGen: C0086652; Orphanet: 582; OMIM: 253010
Name:
GM1 gangliosidosis
Identifiers:
MONDO: MONDO:0018149; MedGen: C0085131

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003490040Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(Aug 20, 2024) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical 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

Novel beta-galactosidase gene mutation p.W273R in a woman with mucopolysaccharidosis type IVB (Morquio B) and lack of response to in vitro chaperone treatment of her skin fibroblasts.

Gucev ZS, Tasic V, Jancevska A, Zafirovski G, Kremensky I, Sinigerska I, Nanba E, Higaki K, Gucev F, Suzuki Y.

Am J Med Genet A. 2008 Jul 1;146A(13):1736-40. doi: 10.1002/ajmg.a.32318.

PubMed [citation]
PMID:
18546276
See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003490040.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 281 of the GLB1 protein (p.His281Arg). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with GLB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2173809). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt GLB1 protein function with a positive predictive value of 95%. This variant disrupts the p.His281 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11511921, 18546276, 21214877, 21497194). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Jun 29, 2025