rs121918181

Positions:

chr7-65979782-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000181.4(GUSB):c.526C>T(p.Leu176Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000477 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 7.42

Variant links:

Genes affected

GUSB (HGNC:4696): (glucuronidase beta) This gene encodes a hydrolase that degrades glycosaminoglycans, including heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate. The enzyme forms a homotetramer that is localized to the lysosome. Mutations in this gene result in mucopolysaccharidosis type VII. Alternative splicing results in multiple transcript variants. There are many pseudogenes of this locus in the human genome.[provided by RefSeq, May 2014]

GUSB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.946

PP5

Variant 7-65979782-G-A is Pathogenic according to our data. Variant chr7-65979782-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-65979782-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUSB	NM_000181.4 linkuse as main transcript	c.526C>T	p.Leu176Phe	missense_variant	3/12	ENST00000304895.9	NP_000172.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUSB	ENST00000304895.9 linkuse as main transcript	c.526C>T	p.Leu176Phe	missense_variant	3/12	1	NM_000181.4	ENSP00000302728	P1	P08236-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000558

AC:

AN:

250940

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000458

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.0000718

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 7

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2003	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2023	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 176 of the GUSB protein (p.Leu176Phe). This variant is present in population databases (rs121918181, gnomAD 0.009%). This missense change has been observed in individual(s) with mucopolysaccharidosis VII (PMID: 7573038, 8089138, 8644704, 12859417, 19224584). It has also been observed to segregate with disease in related individuals. This variant is also known as 552C>T. ClinVar contains an entry for this variant (Variation ID: 905). 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 GUSB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects GUSB function (PMID: 8089138, 12403825). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jan 21, 2020	This variant was observed in compound heterozygosity with variant c.1145G>A -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 19, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 19, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	Published functional studies demonstrate a damaging effect (Tomatsu et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); Reported as the most common variant among patients with MPS VII (Tomatsu et al., 2009); This variant is associated with the following publications: (PMID: 7573038, 8089138, 31980526, 34022924, 31589614, 12859417, 8644704, 19224584, 12403825) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 08, 2013	- -

Mucopolysaccharidosis type 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Aug 16, 2019

Variant summary: GUSB c.526C>T (p.Leu176Phe) results in a non-conservative amino acid change located in the Glycosyl hydrolases family 2, sugar binding domain (IPR006104) 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 5.6e-05 in 250940 control chromosomes (gnomAD). c.526C>T has been reported in the literature in multiple individuals affected with Mucopolysaccharidosis Type VII (Sly Syndrome) (Wu_1994, Vervoort_1996, Schwartz_2003, Montano_2016). These data indicate that the variant is very likely to be associated with disease. Functional studies found the variant to have <10% of normal activity (Wu_1994, Puxan_2018). In addition, a knock-in mouse model with the L175F mutation, corresponding to the L176F variant in humans, exhibited phenotypic characteristics typical of Mucopolysaccharidosis Type VII (Tomatsu_2002). A ClinVar submission (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

GUSB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 11, 2023

The GUSB c.526C>T variant is predicted to result in the amino acid substitution p.Leu176Phe. This variant has been reported to be causative for mucopolysaccharidosis type VII (Vervoort et al. 1995. PubMed ID: 7573038; Vervoort et al. 1996. PubMed ID: 8644704; Tomatsu et al. 2009. PubMed ID: 19224584; Wu et al. 1994 PubMed ID: 8089138; Bayo-Puxan et al. 2018. PMID: 30413728; Schwartz et al. 2003 PMID: 12859417). Cultured fibroblasts derived from patients homozygous for this variant showed that this variant has about 2% of normal beta-glucuronidase activity (Bayo-Puxan et al. 2018. PMID: 30413728; Tomatsu et al. 2009. PubMed ID: 19224584). The mouse model of homozygous p.Leu176Phe had low level of residual enzymatic activity and a milder phenotype (Tomatsu et al. 2002. PubMed ID: 12403825). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD. In summary, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.6

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.77

MVP

0.98

MPC

1.3

ClinPred

0.84

GERP RS

5.3

Varity_R

0.94

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over