NM_000181.4(GUSB):c.1831C>T (p.Arg611Trp) AND Mucopolysaccharidosis type 7

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: May 14, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000000945.10

Allele description [Variation Report for NM_000181.4(GUSB):c.1831C>T (p.Arg611Trp)]

NM_000181.4(GUSB):c.1831C>T (p.Arg611Trp)

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.1831C>T (p.Arg611Trp)

HGVS:

NC_000007.14:g.65961022G>A
NG_016197.1:g.26293C>T
NG_051954.1:g.92924G>A
NM_000181.4:c.1831C>TMANE SELECT
NM_001284290.2:c.1393C>T
NM_001293104.2:c.1261C>T
NM_001293105.2:c.1174C>T
NP_000172.2:p.Arg611Trp
NP_001271219.1:p.Arg465Trp
NP_001280033.1:p.Arg421Trp
NP_001280034.1:p.Arg392Trp
NC_000007.13:g.65426009G>A
NR_120531.2:n.1776C>T
P08236:p.Arg611Trp

Protein change:

R392W; ARG611TRP

Links:

UniProtKB: P08236#VAR_003199; OMIM: 611499.0005; dbSNP: rs121918176

NCBI 1000 Genomes Browser:

rs121918176

Molecular consequence:

NM_000181.4:c.1831C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284290.2:c.1393C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293104.2:c.1261C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293105.2:c.1174C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_120531.2:n.1776C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Mucopolysaccharidosis type 7 (MPS7)
Synonyms:: MPS VII; Mucopolysaccharidosis type VII; MPS 7; 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
SCV000021095	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1993)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002125034	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 28, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 8111413, 28492532
SCV005185834	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (May 14, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000021095

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1993)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV002125034

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 28, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV005185834

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(May 14, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Mutational studies in a patient with the hydrops fetalis form of mucopolysaccharidosis type VII.

Wu BM, Sly WS.

Hum Mutat. 1993;2(6):446-57.

PubMed [citation]

PMID:: 8111413

Details of each submission

From OMIM, SCV000021095.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the arg611-to-trp (R611W) mutation in the GUSB gene that was found in compound heterozygous state in a patient with severe mucopolysaccharidosis type VII (MPS7; 253220) by Wu and Sly (1993), see 611499.0004.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002125034.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine with tryptophan at codon 611 of the GUSB protein (p.Arg611Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121918176, ExAC 0.001%). This missense change has been observed in individual(s) with mucopolysaccharidosis type VII (PMID: 8111413). ClinVar contains an entry for this variant (Variation ID: 897). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects GUSB function (PMID: 8111413). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005185834.1

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

Description

Variant summary: GUSB c.1831C>T (p.Arg611Trp) results in a non-conservative amino acid change located in the Glycoside hydrolase family 2, catalytic domain (IPR006103) 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 4e-06 in 251484 control chromosomes (gnomAD). c.1831C>T has been reported in the literature in an individuals affected with Mucopolysaccharidosis Type VII (Sly Syndrome; Wu_1993). These data do not allow any conclusion about variant significance. This publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in 0% of normal enzymatic activity. The following publication has been ascertained in the context of this evaluation (PMID: 8111413). ClinVar contains an entry for this variant (Variation ID: 897). 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

Last Updated: Sep 29, 2024

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