NM_000181.4(GUSB):c.1856C>T (p.Ala619Val) AND Mucopolysaccharidosis type 7

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 7, 2023
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:: RCV000000941.10

Allele description [Variation Report for NM_000181.4(GUSB):c.1856C>T (p.Ala619Val)]

NM_000181.4(GUSB):c.1856C>T (p.Ala619Val)

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.1856C>T (p.Ala619Val)

HGVS:

NC_000007.14:g.65960997G>A
NG_016197.1:g.26318C>T
NG_051954.1:g.92899G>A
NM_000181.3:c.1856C>T
NM_000181.4:c.1856C>TMANE SELECT
NM_001284290.2:c.1418C>T
NM_001293104.2:c.1286C>T
NM_001293105.2:c.1199C>T
NP_000172.2:p.Ala619Val
NP_001271219.1:p.Ala473Val
NP_001280033.1:p.Ala429Val
NP_001280034.1:p.Ala400Val
NC_000007.13:g.65425984G>A
NR_120531.2:n.1801C>T
P08236:p.Ala619Val

Protein change:

A400V; ALA619VAL

Links:

UniProtKB: P08236#VAR_003200; OMIM: 611499.0001; dbSNP: rs121918172

NCBI 1000 Genomes Browser:

rs121918172

Molecular consequence:

NM_000181.4:c.1856C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001284290.2:c.1418C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293104.2:c.1286C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001293105.2:c.1199C>T - missense variant - [Sequence Ontology: SO:0001583]
NR_120531.2:n.1801C>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
SCV000021091	OMIM	no assertion criteria provided	Pathogenic (Jan 1, 1991)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001589359	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 7, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 30653816, 1702266, 1779626, 2115490, 7633414, 19224584, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000021091

OMIM

no assertion criteria provided

Pathogenic
(Jan 1, 1991)

germline

literature only

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

SCV001589359

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 7, 2023)

germline

clinical testing

PubMed (7)
[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	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

Oral manifestations in patients and dogs with mucopolysaccharidosis Type VII.

Kantaputra PN, Smith LJ, Casal ML, Kuptanon C, Chang YC, Nampoothiri S, Paiyarom A, Veerasakulwong T, Trachoo O, Ketudat Cairns JR, Chinadet W, Tanpaiboon P.

Am J Med Genet A. 2019 Mar;179(3):486-493. doi: 10.1002/ajmg.a.61034. Epub 2019 Jan 17.

PubMed [citation]

PMID:: 30653816
PMCID:: PMC6374205

Mucopolysaccharidosis type VII: characterization of mutations and molecular heterogeneity.

Tomatsu S, Fukuda S, Sukegawa K, Ikedo Y, Yamada S, Yamada Y, Sasaki T, Okamoto H, Kuwahara T, Yamaguchi S, et al.

Am J Hum Genet. 1991 Jan;48(1):89-96.

PubMed [citation]

PMID:: 1702266
PMCID:: PMC1682743

See all PubMed Citations (7)

Details of each submission

From OMIM, SCV000021091.2

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

Description

In a 24-year-old Japanese man with mucopolysaccharidosis type VII (MPS7; 253220), Tomatsu et al. (1991) identified a homozygous C-to-T transition in the GUSB gene, resulting in an ala619-to-val (A619V) substitution in a highly conserved region among human, rat, and E. coli. In vitro functional expression studies showed that the mutant protein resulted in decreased enzyme activity. The change resulted in loss of the cleavage site for Fnu4HI in the mutated cDNA. The patient had unusual facies, hepatomegaly, umbilical herniation, short stature, slight bone deformity, mental retardation, and coarse metachromatic granules in white blood cells. Beta-glucuronidase activity was about 2% of normal values.

#	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, SCV001589359.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 619 of the GUSB protein (p.Ala619Val). This variant is present in population databases (rs121918172, gnomAD 0.006%). This missense change has been observed in individual(s) with mucopolysaccharidosis Type VII (PMID: 1779626, 2115490, 30653816). ClinVar contains an entry for this variant (Variation ID: 893). 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 not expected to disrupt GUSB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GUSB function (PMID: 1702266, 1779626, 2115490, 7633414, 19224584). For these reasons, this variant has been classified as 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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