NM_000404.4(GLB1):c.442C>A (p.Arg148Ser) AND Mucopolysaccharidosis, MPS-IV-B

Clinical significance:Pathogenic (Last evaluated: May 11, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000780304.1

Allele description [Variation Report for NM_000404.4(GLB1):c.442C>A (p.Arg148Ser)]

NM_000404.4(GLB1):c.442C>A (p.Arg148Ser)

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.442C>A (p.Arg148Ser)
HGVS:
  • NC_000003.12:g.33068245G>T
  • NG_009005.1:g.33958C>A
  • NM_000404.4:c.442C>AMANE SELECT
  • NM_001079811.3:c.352C>A
  • NM_001135602.3:c.246-2688C>A
  • NM_001317040.2:c.586C>A
  • NM_001393580.1:c.442C>A
  • NP_000395.3:p.Arg148Ser
  • NP_001073279.2:p.Arg118Ser
  • NP_001303969.2:p.Arg196Ser
  • NP_001380509.1:p.Arg148Ser
  • NC_000003.11:g.33109737G>T
  • NM_000404.2:c.442C>A
Protein change:
R118S
Links:
dbSNP: rs192732174
NCBI 1000 Genomes Browser:
rs192732174
Molecular consequence:
  • NM_001135602.3:c.246-2688C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000404.4:c.442C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079811.3:c.352C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317040.2:c.586C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001393580.1:c.442C>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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000917466Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(May 11, 2018)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Impaired elastic-fiber assembly by fibroblasts from patients with either Morquio B disease or infantile GM1-gangliosidosis is linked to deficiency in the 67-kD spliced variant of beta-galactosidase.

Hinek A, Zhang S, Smith AC, Callahan JW.

Am J Hum Genet. 2000 Jul;67(1):23-36. Epub 2000 Jun 6.

PubMed [citation]
PMID:
10841810
PMCID:
PMC1287082

Four novel mutations in patients from the Middle East with the infantile form of GM1-gangliosidosis.

Georgiou T, Drousiotou A, Campos Y, Caciotti A, Sztriha L, Gururaj A, Ozand P, Zammarchi E, Morrone A, D'Azzo A.

Hum Mutat. 2004 Oct;24(4):352. Erratum in: Hum Mutat. 2004 Dec;24(6):536-7.

PubMed [citation]
PMID:
15365997
See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917466.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

Variant summary: GLB1 c.442C>A (p.Arg148Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase 35 catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 276992 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing GM1 gangliosidosis (4.3e-05 vs 2.00e-03), allowing no conclusion about variant significance. The variant, c.442C>A, has been reported in the literature in several individuals affected with GM1 gangliosidosis (Zhang_2000, Hofer_2010, Nestrasil_2018). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein maturation and enzyme activity, with both being significantly reduced in the presence of the variant (Zhang_2000). Additionally, other variants at the Arg148 residue have been reported as associated with disease (p.Arg148Cys and p.Arg148His), suggesting that this codon is important for function. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.

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

Last Updated: Nov 27, 2021

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