Variant summary: HEXB c.1598G>A (p.Arg533His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251256 control chromosomes. c.1598G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with adult onset Sandhoff Disease (example, Yoshizawa_2002, Khani_2021). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1597C>T, p.Arg533Cys), supporting the critical relevance of codon 533 to HEXB protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a severely decreased beta Hexosaminidase enzyme activity in an in-vitro (COS1 cells) experimental system (example, Yoshizawa_2002). The following publications have been ascertained in the context of this evaluation (PMID: 33824075, 29448188, 31995250, 23127958, 11897243, 22848519). ClinVar contains an entry for this variant (Variation ID: 1301333). Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000521.4(HEXB):c.1598G>A (p.Arg533His)
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.
(5)
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
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000521.4(HEXB):c.1598G>A (p.Arg533His)
Variation ID: 1301333 Accession: VCV001301333.8
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q13.3 5: 74720732 (GRCh38) [ NCBI UCSC ] 5: 74016557 (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 Oct 30, 2021 Sep 16, 2024 Jul 3, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000521.4:c.1598G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000512.2:p.Arg533His missense NM_001292004.2:c.923G>A NP_001278933.1:p.Arg308His missense NC_000005.10:g.74720732G>A NC_000005.9:g.74016557G>A NG_009770.2:g.85710G>A NG_011531.1:g.51486C>T - Protein change
- R308H, R533H
- Other names
-
p.Arg533His
- Canonical SPDI
- NC_000005.10:74720731:G:A
-
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) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
- 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. |
|||
| HEXB | - | - |
GRCh38 GRCh37 |
797 | 821 | |
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/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Jul 3, 2024 | RCV001732819.7 | |
| Pathogenic (1) |
criteria provided, single submitter
|
May 10, 2023 | RCV003481126.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jul 03, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983505.2
First in ClinVar: Oct 30, 2021 Last updated: Sep 16, 2024 |
Comment:
Variant summary: HEXB c.1598G>A (p.Arg533His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging … (more)
Variant summary: HEXB c.1598G>A (p.Arg533His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251256 control chromosomes. c.1598G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with adult onset Sandhoff Disease (example, Yoshizawa_2002, Khani_2021). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1597C>T, p.Arg533Cys), supporting the critical relevance of codon 533 to HEXB protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a severely decreased beta Hexosaminidase enzyme activity in an in-vitro (COS1 cells) experimental system (example, Yoshizawa_2002). The following publications have been ascertained in the context of this evaluation (PMID: 33824075, 29448188, 31995250, 23127958, 11897243, 22848519). ClinVar contains an entry for this variant (Variation ID: 1301333). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Apr 28, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002789456.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(May 10, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not provided
Affected status: unknown
Allele origin:
germline
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226556.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PM2, PM3, PM5, PS3
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Sep 28, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV003525922.2
First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024 |
Comment:
This missense change has been observed in individual(s) with Sandhoff disease (PMID: 11897243, 18758829). In at least one individual the data is consistent with being … (more)
This missense change has been observed in individual(s) with Sandhoff disease (PMID: 11897243, 18758829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1301333). 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) performed at Invitae indicates that this missense variant is expected to disrupt HEXB protein function. Experimental studies have shown that this missense change affects HEXB function (PMID: 11897243). This variant disrupts the p.Arg533 amino acid residue in HEXB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21567908, 22848519, 23010210, 27682710). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the HEXB protein (p.Arg533His). (less)
|
|
|
Likely pathogenic
(Sep 12, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV004704525.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Comment:
ACMG criteria used to clasify this variant: PP3_STR, PM1, PM2_SUP
Clinical Features:
Elevated circulating creatine kinase concentration (present) , Upper limb amyotrophy (present) , Muscle weakness (present)
|
Comment:
Comment:
PM2, PM3, PM5, PS3
Comment:
This missense change has been observed in individual(s) with Sandhoff disease (PMID: 11897243, 18758829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1301333). 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) performed at Invitae indicates that this missense variant is expected to disrupt HEXB protein function. Experimental studies have shown that this missense change affects HEXB function (PMID: 11897243). This variant disrupts the p.Arg533 amino acid residue in HEXB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21567908, 22848519, 23010210, 27682710). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the HEXB protein (p.Arg533His).
Comment:
ACMG criteria used to clasify this variant: PP3_STR, PM1, PM2_SUP
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:
Variant summary: HEXB c.1598G>A (p.Arg533His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251256 control chromosomes. c.1598G>A has been reported in the literature as a compound heterozygous genotype in at-least two individuals affected with adult onset Sandhoff Disease (example, Yoshizawa_2002, Khani_2021). A different variant affecting the same codon has been classified as pathogenic by our lab (c.1597C>T, p.Arg533Cys), supporting the critical relevance of codon 533 to HEXB protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a severely decreased beta Hexosaminidase enzyme activity in an in-vitro (COS1 cells) experimental system (example, Yoshizawa_2002). The following publications have been ascertained in the context of this evaluation (PMID: 33824075, 29448188, 31995250, 23127958, 11897243, 22848519). ClinVar contains an entry for this variant (Variation ID: 1301333). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
PM2, PM3, PM5, PS3
Comment:
This missense change has been observed in individual(s) with Sandhoff disease (PMID: 11897243, 18758829). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1301333). 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) performed at Invitae indicates that this missense variant is expected to disrupt HEXB protein function. Experimental studies have shown that this missense change affects HEXB function (PMID: 11897243). This variant disrupts the p.Arg533 amino acid residue in HEXB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21567908, 22848519, 23010210, 27682710). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 533 of the HEXB protein (p.Arg533His).
Comment:
ACMG criteria used to clasify this variant: PP3_STR, PM1, PM2_SUP
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| A case of adult onset Sandhoff disease that mimics Brown-Vialetto-Van Laere syndrome. | Khani M | Neuromuscular disorders : NMD | 2021 | PMID: 33824075 |
| Natural History of Adult Patients with GM2 Gangliosidosis. | Masingue M | Annals of neurology | 2020 | PMID: 31995250 |
| Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. | Ou L | Molecular genetics and metabolism reports | 2019 | PMID: 31367523 |
| Genotype, phenotype and in silico pathogenicity analysis of HEXB mutations: Panel based sequencing for differential diagnosis of gangliosidosis. | Mahdieh N | Clinical neurology and neurosurgery | 2018 | PMID: 29448188 |
| Co-existence of phenylketonuria either with maple syrup urine disease or Sandhoff disease in two patients from Iran: emphasizing the role of consanguinity. | Abiri M | Journal of pediatric endocrinology & metabolism : JPEM | 2016 | PMID: 27682710 |
| Characterization of the mutant β-subunit of β-hexosaminidase for dimer formation responsible for the adult form of Sandhoff disease with the motor neuron disease phenotype. | Yamada K | Journal of biochemistry | 2013 | PMID: 23127958 |
| Integrated multiplex ligation dependent probe amplification (MLPA) assays for the detection of alterations in the HEXB, GM2A and SMARCAL1 genes to support the diagnosis of Morbus Sandhoff, M. Tay-Sachs variant AB and Schimke immuno-osseous dysplasia in humans. | Sobek AK | Molecular and cellular probes | 2013 | PMID: 23010210 |
| Novel Mutations in Sandhoff Disease: A Molecular Analysis among Iranian Cohort of Infantile Patients. | Aryan H | Iranian journal of public health | 2012 | PMID: 23113155 |
| Sequence and copy number analyses of HEXB gene in patients affected by Sandhoff disease: functional characterization of 9 novel sequence variants. | Zampieri S | PloS one | 2012 | PMID: 22848519 |
| GM2 gangliosidosis in Saudi Arabia: multiple mutations and considerations for future carrier screening. | Kaya N | American journal of medical genetics. Part A | 2011 | PMID: 21567908 |
| Molecular and functional analysis of the HEXB gene in Italian patients affected with Sandhoff disease: identification of six novel alleles. | Zampieri S | Neurogenetics | 2009 | PMID: 18758829 |
| Compound heterozygosity with two novel mutations in the HEXB gene produces adult Sandhoff disease presenting as a motor neuron disease phenotype. | Yoshizawa T | Journal of the neurological sciences | 2002 | PMID: 11897243 |
| click to load more click to collapse | ||||
Text-mined citations for rs1291555996 ...
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 Sep 29, 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.