rs1553612189

Variant names:

• chr3-33068821-A-G
• rs1553612189
• NM_000404.4:c.395T>C

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Very_Strong

The NM_000404.4(GLB1):​c.395T>C​(p.Met132Thr) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLB1 NM_000404.4 missense, splice_region
• Scores: Splicing: ADA: 0.5759
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 U:1
• Conservation: PhyloP100: 9.23
• Publications: 1 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 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000404.4
• PM2: Very rare variant in population databases, with high coverage
• 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: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 3-33068821-A-G is Pathogenic according to our data. Variant chr3-33068821-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556862.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.395T>C	p.Met132Thr	missense_variant, splice_region_variant	Exon 3 of 16	ENST00000307363.10	NP_000395.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLB1	ENST00000307363.10	c.395T>C	p.Met132Thr	missense_variant, splice_region_variant	Exon 3 of 16	1	NM_000404.4	ENSP00000306920.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-IV-B Pathogenic:1

Sep 03, 2021

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: GLB1 c.395T>C (p.Met132Thr) results in a non-conservative amino acid change located in the Glycoside hydrolase 35, catalytic domain (IPR031330) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249434 control chromosomes. c.395T>C has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with infantile onset Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (example, Hofer_2009). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 4.3% of normal beta galactosidase enzyme activity in transiently transfected COS-1 cells (Hofer_2009). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above (ACMG PS3, PM2, PM3), the variant was classified as likely pathogenic. -

Infantile GM1 gangliosidosis Pathogenic:1

May 04, 2022

Mendelics

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 Uncertain:1

Feb 21, 2018

Counsyl

Significance: Uncertain significance

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		9.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.3	D;D;D;D
REVEL	Pathogenic	0.94
Sift	Benign	0.031	D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;.
Vest4		0.94
MutPred		0.73		Loss of stability (P = 0.0757);.;.;.;
MVP		0.99
MPC		0.35
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.95
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.58
dbscSNV1_RF	Benign	0.57
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: rs1553612189; hg19: chr3-33110313;