rs121918176

Positions:

chr7-65961022-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_000181.4(GUSB):c.1831C>T(p.Arg611Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,612,522 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

GUSB
NM_000181.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 4.05

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 Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.967

PP5

Variant 7-65961022-G-A is Pathogenic according to our data. Variant chr7-65961022-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 897.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUSB	NM_000181.4 linkuse as main transcript	c.1831C>T	p.Arg611Trp	missense_variant	12/12	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.1831C>T	p.Arg611Trp	missense_variant	12/12	1	NM_000181.4	ENSP00000302728	P1	P08236-1

Frequencies

GnomAD3 genomes

AF:

0.00000663

AC:

AN:

150810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251484

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461712

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000663

AC:

AN:

150810

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73428

show subpopulations

Gnomad4 AFR

AF:

0.0000244

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000290

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucopolysaccharidosis type 7

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2021	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 14, 2024	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.3

D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MVP

0.98

MPC

1.2

ClinPred

1.0

GERP RS

4.0

Varity_R

0.95

gMVP

0.86

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