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NM_000404.4(GLB1):c.521A>C (p.Tyr174Ser) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
May 6, 2021
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:
RCV002024552.7

Allele description [Variation Report for NM_000404.4(GLB1):c.521A>C (p.Tyr174Ser)]

NM_000404.4(GLB1):c.521A>C (p.Tyr174Ser)

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.521A>C (p.Tyr174Ser)
HGVS:
  • NC_000003.12:g.33065494T>G
  • NG_009005.1:g.36709A>C
  • NM_000404.4:c.521A>CMANE SELECT
  • NM_001079811.3:c.431A>C
  • NM_001135602.3:c.309A>C
  • NM_001317040.2:c.665A>C
  • NM_001393580.1:c.521A>C
  • NP_000395.3:p.Tyr174Ser
  • NP_001073279.2:p.Tyr144Ser
  • NP_001129074.2:p.Leu103=
  • NP_001303969.2:p.Tyr222Ser
  • NP_001380509.1:p.Tyr174Ser
  • NC_000003.11:g.33106986T>G
Protein change:
Y144S
Links:
dbSNP: rs2125543580
NCBI 1000 Genomes Browser:
rs2125543580
Molecular consequence:
  • NM_000404.4:c.521A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001079811.3:c.431A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001317040.2:c.665A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001393580.1:c.521A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001135602.3:c.309A>C - synonymous variant - [Sequence Ontology: SO:0001819]

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
SCV002308938Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Likely pathogenic
(May 6, 2021) 		germlineclinical testing

PubMed (3)
[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

Paramagnetic signals in the globus pallidus as late radiographic sign of juvenile-onset GM1 gangliosidosis.

Takenouchi T, Kosaki R, Nakabayashi K, Hata K, Takahashi T, Kosaki K.

Pediatr Neurol. 2015 Feb;52(2):226-9. doi: 10.1016/j.pediatrneurol.2014.09.022. Epub 2014 Oct 16.

PubMed [citation]
PMID:
25443580

Hypomyelinating disorders in China: The clinical and genetic heterogeneity in 119 patients.

Ji H, Li D, Wu Y, Zhang Q, Gu Q, Xie H, Ji T, Wang H, Zhao L, Zhao H, Yang Y, Feng H, Xiong H, Ji J, Yang Z, Kou L, Li M, Bao X, Chang X, Zhang Y, Li L, Li H, et al.

PLoS One. 2018;13(2):e0188869. doi: 10.1371/journal.pone.0188869.

PubMed [citation]
PMID:
29451896
PMCID:
PMC5815574
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002308938.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces tyrosine with serine at codon 174 of the GLB1 protein (p.Tyr174Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with GLB1-related conditions. 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. This variant disrupts the p.Tyr174 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25443580, 29451896). 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: May 16, 2025