rs201807974

chr3-32997296-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000404.4(GLB1):c.1783C>T(p.Arg595Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000663 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R595Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: GLB1 NM_000404.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-32997295-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 932727.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3002599).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLB1	NM_000404.4	c.1783C>T	p.Arg595Trp	missense_variant	16/16	ENST00000307363.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLB1	ENST00000307363.10	c.1783C>T	p.Arg595Trp	missense_variant	16/16	1	NM_000404.4	P2
GLB1	ENST00000307377.12	c.1390C>T	p.Arg464Trp	missense_variant	13/13	1
GLB1	ENST00000399402.7	c.1693C>T	p.Arg565Trp	missense_variant	16/16	2		A2

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.000955

GnomAD3 exomes AF: 0.000120 AC: 30 AN: 249362 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135308

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000753

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: 0.0000265

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461768 Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38 AN XY: 727186

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74478

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000653

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: 0.000945

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.0000331 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 22, 2021	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 16, 2021

Variant summary: GLB1 c.1783C>T (p.Arg595Trp) results in a non-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 0.00012 in 249362 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in GLB1 causing Mucopolysaccharidosis Type IVB (Morquio Syndrome B) (0.00012 vs 0.00091), allowing no conclusion about variant significance. c.1783C>T has been reported in the literature as a compound heterozygous genotype with another pathogenic allele in trans in the clinically unaffected father of an individual with GM1 gangliosidosis (Gort_2007). The disease in the affected individual was attributed to a biallelic genotype comprising the pathogenic allele from this unaffected father and another pathogenic allele from the obligate carrier mother, but not to this variant. Further biochemical workup of the healthy father revealed a pseudodeficient beta galactosidase enzyme activity in both his leukocytes and plasma. These report(s) do not provide unequivocal conclusions about association of the variant with Mucopolysaccharidosis Type IVB (Morquio Syndrome B). At least one publication reports experimental evidence evaluating an impact on protein function (Gort_2007). The most pronounced variant effect results in 33-59% of normal enzyme activity when this variant was traniently expressed in-vitro. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a pseudodeficiency allele of uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 10, 2022

The c.1783C>T (p.R595W) alteration is located in exon 16 (coding exon 16) of the GLB1 gene. This alteration results from a C to T substitution at nucleotide position 1783, causing the arginine (R) at amino acid position 595 to be replaced by a tryptophan (W). The alteration is predicted deleterious by in silico models:_x000D_ The p.R595W alteration is predicted to be possibly damaging by Polyphen and deleterious by SIFT in silico analyses. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Oct 21, 2020

ACMG classification criteria: PM2, PM3 -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 595 of the GLB1 protein (p.Arg595Trp). This variant is present in population databases (rs201807974, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with GLB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 550288). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLB1 protein function. Experimental studies have shown that this missense change affects GLB1 function (PMID: 17661814). 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. -

GM1 gangliosidosis type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Benign	0.061
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.28	N
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	0.081	D
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.032	D;D;D
Sift4G	Uncertain	0.045	D;T;D
Polyphen		1.0	.;.;D
Vest4		0.81
MutPred		0.72		Loss of solvent accessibility (P = 0.0036);.;.;
MVP		0.92
MPC		0.85
ClinPred		0.76	D
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs201807974; hg19: chr3-33038788;