rs371582179

Variant names:

• chr3-33014057-T-C
• rs371582179
• NM_000404.4:c.1733A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PP2 PP3 PP5_Very_Strong

The NM_000404.4(GLB1):​c.1733A>G​(p.Lys578Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000113 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K578Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GLB1 NM_000404.4 missense, splice_region
• Scores: Splicing: ADA: 0.9955
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 7.54
• Publications: 10 publications found

Genes affected

GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]

GLB1 Gene-Disease associations (from GenCC):

• GM1 gangliosidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
• GM1 gangliosidosis type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mucopolysaccharidosis type 4B

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• GM1 gangliosidosis type 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• GM1 gangliosidosis type 2

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000404.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 110 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 0.79419 (below the threshold of 3.09). Trascript score misZ: 1.1264 (below the threshold of 3.09). GenCC associations: The gene is linked to mucopolysaccharidosis type 4B, GM1 gangliosidosis, GM1 gangliosidosis type 2, GM1 gangliosidosis type 3, GM1 gangliosidosis type 1.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 3-33014057-T-C is Pathogenic according to our data. Variant chr3-33014057-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 252985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLB1	NM_000404.4	c.1733A>G	p.Lys578Arg	missense_variant, splice_region_variant	Exon 15 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.1733A>G	p.Lys578Arg	missense_variant, splice_region_variant	Exon 15 of 16	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000364 AC: 9 AN: 247460 AF XY: 0.0000372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000719

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000119 AC: 174 AN: 1461892 Hom.: 0 Cov.: 30 AF XY: 0.000107 AC XY: 78 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000149 AC: 166 AN: 1112012

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74360

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000845 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Jul 09, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 Pathogenic:2

Mar 08, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GM1 gangliosidosis Pathogenic:1 Other:1

Aug 13, 2024

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLB1 c.1733A>G (p.Lys578Arg) results in a conservative amino acid change located in the Beta-galactosidase jelly roll domain (IPR025300) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 247460 control chromosomes. c.1733A>G has been reported in the literature in multiple individuals affected with infantile and late-infantile/juvenile GM1 gangliosidosis (Boustany_1993, Caciotti_2011, Nestrasil_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Caciotti_2011). The following publications have been ascertained in the context of this evaluation (PMID: 8213816, 21497194, 29352662). ClinVar contains an entry for this variant (Variation ID: 252985). Based on the evidence outlined above, the variant was classified as pathogenic. -

-

GenomeConnect - GM1

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant identified in multiple registry participants. Variant classified as Pathogenic and reported on 12-08-2021 by Blueprint Genetics. Variant classidied as Pathogenic and reported on 08-11-2016 by lab or GTR ID Hudson Alpha. GenomeConnect - GM1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Inborn genetic diseases Pathogenic:1

Nov 02, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1733A>G (p.K578R) alteration is located in exon 15 (coding exon 15) of the GLB1 gene. This alteration results from a A to G substitution at nucleotide position 1733, causing the lysine (K) at amino acid position 578 to be replaced by an arginine (R). Based on data from gnomAD, the G allele has an overall frequency of 0.004% (9/247460) total alleles studied. The highest observed frequency was 0.007% (8/111208) of European (non-Finnish) alleles. This variant has been reported in the homozygous state, and in conjunction with a second variant in GLB1, in multiple individuals with GM1 gangliosidosis (Boustany, 1993; Caciotti, 2011; Utz, 2015; Jarnes Utz, 2017; Bowling, 2017; Nestrasil, 2018; Ou, 2019; Arash-Kaps, 2019; King, 2020; Tebani, 2022). This amino acid position is highly conserved in available vertebrate species. In vitro studies have demonstrated that this alteration has reduced enzymatic activity (Boustany, 1993). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 578 of the GLB1 protein (p.Lys578Arg). This variant is present in population databases (rs371582179, gnomAD 0.007%). This missense change has been observed in individual(s) with GM1 gangliosidosis (PMID: 8213816, 21497194, 25557439). ClinVar contains an entry for this variant (Variation ID: 252985). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GLB1 function (PMID: 8213816). This variant disrupts the p.Lys578 amino acid residue in GLB1. Other variant(s) that disrupt this residue have been observed in individuals with GLB1-related conditions (PMID: 30267299), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

GM1 gangliosidosis type 2 Pathogenic:1

Jul 14, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.79	.;.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Pathogenic	1.0	D
PhyloP100		7.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.95
MVP		0.98
MPC		0.78
ClinPred		0.92	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Other links and lift over

dbSNP: rs371582179; hg19: chr3-33055549;