NM_000181.4(GUSB):c.724+1G>T AND Mucopolysaccharidosis type 7

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV003226648.3

Allele description [Variation Report for NM_000181.4(GUSB):c.724+1G>T]

NM_000181.4(GUSB):c.724+1G>T

Gene:

GUSB:glucuronidase beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q11.21

Genomic location:

Preferred name:

NM_000181.4(GUSB):c.724+1G>T

HGVS:

NC_000007.14:g.65979398C>A
NG_016197.1:g.7917G>T
NM_000181.4:c.724+1G>TMANE SELECT
NM_001284290.2:c.474+436G>T
NM_001293104.2:c.154+1G>T
NM_001293105.2:c.67+826G>T
NC_000007.13:g.65444385C>A
NM_000181.3:c.724+1G>T

Links:

dbSNP: rs2116026958

NCBI 1000 Genomes Browser:

rs2116026958

Molecular consequence:

NM_001284290.2:c.474+436G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001293105.2:c.67+826G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000181.4:c.724+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001293104.2:c.154+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Mucopolysaccharidosis type 7 (MPS7)
Synonyms:: BETA-GLUCURONIDASE DEFICIENCY; GUSB DEFICIENCY; MPS VII; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009662; MedGen: C0085132; Orphanet: 584; OMIM: 253220

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003922562	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Mar 14, 2023)	germline	clinical testing	Citation Link,
SCV004627864	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16199547, 19224584, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003922562

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Mar 14, 2023)

germline

clinical testing

Citation Link,

SCV004627864

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 22, 2024)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome).

Tomatsu S, Montaño AM, Dung VC, Grubb JH, Sly WS.

Hum Mutat. 2009 Apr;30(4):511-9. doi: 10.1002/humu.20828. Review.

PubMed [citation]

PMID:: 19224584
PMCID:: PMC3048808

See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003922562.1

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

Description

Variant summary: GUSB c.724+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251058 control chromosomes. To our knowledge, no occurrence of c.724+1G>T in individuals affected with Mucopolysaccharidosis Type VII (Sly Syndrome) and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was 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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV004627864.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change affects a donor splice site in intron 4 of the GUSB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GUSB are known to be pathogenic (PMID: 19224584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with GUSB-related conditions. ClinVar contains an entry for this variant (Variation ID: 2501051). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: Jan 13, 2025

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