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.
ClinVar Genomic variation as it relates to human health
NM_000404.4(GLB1):c.1733A>G (p.Lys578Arg)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(9)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
9
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000404.4(GLB1):c.1733A>G (p.Lys578Arg)
Variation ID: 252985 Accession: VCV000252985.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 3p22.3 3: 33014057 (GRCh38) [ NCBI UCSC ] 3: 33055549 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 14, 2016 Oct 26, 2024 Aug 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000404.4:c.1733A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000395.3:p.Lys578Arg missense NM_000404.3:c.1733A>G NM_001079811.3:c.1643A>G NP_001073279.2:p.Lys548Arg missense NM_001135602.3:c.1340A>G NP_001129074.2:p.Lys447Arg missense NM_001317040.2:c.1877A>G NP_001303969.2:p.Lys626Arg missense NM_001393580.1:c.1733A>G NP_001380509.1:p.Lys578Arg missense NC_000003.12:g.33014057T>C NC_000003.11:g.33055549T>C NG_009005.1:g.88146A>G - Protein change
- K578R, K548R, K626R, K447R
- Other names
- -
- Canonical SPDI
- NC_000003.12:33014056:T:C
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00004
The Genome Aggregation Database (gnomAD) 0.00006
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00009
Exome Aggregation Consortium (ExAC) 0.00003
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| GLB1 | - | - |
GRCh38 GRCh37 |
1056 | 1169 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
criteria provided, single submitter
|
Jul 14, 2016 | RCV000239412.4 | |
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 31, 2018 | RCV000665995.4 | |
| Pathogenic (2) |
criteria provided, single submitter
|
Aug 13, 2024 | RCV001192992.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jan 29, 2024 | RCV001061617.6 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 1, 2022 | RCV001200664.27 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 2, 2022 | RCV002518537.3 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Likely pathogenic
(Mar 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile GM1 gangliosidosis
GM1 gangliosidosis type 2 GM1 gangliosidosis type 3 Mucopolysaccharidosis, MPS-IV-B
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000790224.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
|
|
|
Likely pathogenic
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Infantile GM1 gangliosidosis
GM1 gangliosidosis type 2 GM1 gangliosidosis type 3 Mucopolysaccharidosis, MPS-IV-B
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894314.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
|
Pathogenic
(Jul 14, 2016)
|
criteria provided, single submitter
Method: research
|
GM1 gangliosidosis type 2
Affected status: yes
Allele origin:
paternal
|
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Study: CSER-HudsonAlpha
Accession: SCV000297796.4 First in ClinVar: Aug 14, 2016 Last updated: Dec 24, 2022 |
Number of individuals with the variant: 1
Clinical Features:
Delayed speech and language development (present) , Generalized hypotonia (present) , Intellectual disability, moderate (present)
|
|
|
Pathogenic
(Jan 29, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Mucopolysaccharidosis, MPS-IV-B
GM1 gangliosidosis
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001226365.4
First in ClinVar: Apr 15, 2020 Last updated: Feb 28, 2024 |
Comment:
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). … (more)
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. (less)
|
|
|
Pathogenic
(Jan 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001371677.24
First in ClinVar: Jul 16, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 3
|
|
|
Pathogenic
(Aug 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
GM1 gangliosidosis
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001361490.2
First in ClinVar: Jun 22, 2020 Last updated: Oct 26, 2024 |
Comment:
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. … (more)
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. (less)
|
|
|
Pathogenic
(Jul 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024823.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 02, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003708380.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
not provided
(-)
|
no classification provided
Method: phenotyping only
|
GM1 gangliosidosis
Affected status: yes
Allele origin:
maternal,
germline
|
GenomeConnect - GM1
Accession: SCV002047668.2
First in ClinVar: Jan 05, 2022 Last updated: Jan 07, 2023 |
Comment:
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 … (more)
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. (less)
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Abnormality of eye movement (present) , Generalized hypotonia (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: male
Method: Exome Sequencing
Testing laboratory: Blueprint Genetics
Date variant was reported to submitter: 2021-12-08
Testing laboratory interpretation: Pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Abnormal muscle physiology (present) , Cognitive impairment (present) , Abnormality of coordination (present) , Hypertonia (present) , Generalized hypotonia (present)
Indication for testing: Diagnostic
Age: 0-9 years
Sex: female
Method: Genome Sequencing
Testing laboratory: HudsonAlpha Clinical Services Lab, LLC,HudsonAlpha Clinical Services Lab, LLC
Date variant was reported to submitter: 2016-08-11
Testing laboratory interpretation: Pathogenic
|
Comment:
Comment:
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.
Comment:
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.
Comment:
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.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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.
Comment:
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.
Comment:
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.
Comment:
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Disentangling molecular and clinical stratification patterns in beta-galactosidase deficiency. | Tebani A | Journal of medical genetics | 2022 | PMID: 33737400 |
| The juvenile gangliosidoses: A timeline of clinical change. | King KE | Molecular genetics and metabolism reports | 2020 | PMID: 33240792 |
| The Clinical and Molecular Spectrum of GM1 Gangliosidosis. | Arash-Kaps L | The Journal of pediatrics | 2019 | PMID: 31761138 |
| Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. | Ou L | Molecular genetics and metabolism reports | 2019 | PMID: 31367523 |
| Clinical and molecular characteristics of 11 Chinese probands with GM1 gangliosidosis. | Feng Y | Metabolic brain disease | 2018 | PMID: 30267299 |
| Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. | Nestrasil I | Molecular genetics and metabolism | 2018 | PMID: 29352662 |
| Genomic diagnosis for children with intellectual disability and/or developmental delay. | Bowling KM | Genome medicine | 2017 | PMID: 28554332 |
| Infantile gangliosidoses: Mapping a timeline of clinical changes. | Jarnes Utz JR | Molecular genetics and metabolism | 2017 | PMID: 28476546 |
| Biomarkers of central nervous system inflammation in infantile and juvenile gangliosidoses. | Utz JR | Molecular genetics and metabolism | 2015 | PMID: 25557439 |
| Chemical chaperone therapy: chaperone effect on mutant enzyme and cellular pathophysiology in β-galactosidase deficiency. | Higaki K | Human mutation | 2011 | PMID: 21520340 |
| GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. | Caciotti A | Biochimica et biophysica acta | 2011 | PMID: 21497194 |
| Mutations in acid beta-galactosidase cause GM1-gangliosidosis in American patients. | Boustany RM | American journal of human genetics | 1993 | PMID: 8213816 |
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Text-mined citations for rs371582179 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 27, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.