ClinVar Genomic variation as it relates to human health
NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000521.4(HEXB):c.1514G>A (p.Arg505Gln)
Variation ID: 3879 Accession: VCV000003879.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.3 5: 74720648 (GRCh38) [ NCBI UCSC ] 5: 74016473 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 4, 2013 Jun 17, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000521.4:c.1514G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000512.2:p.Arg505Gln missense NM_001292004.2:c.839G>A NP_001278933.1:p.Arg280Gln missense NC_000005.10:g.74720648G>A NC_000005.9:g.74016473G>A NG_009770.2:g.85626G>A NG_011531.1:g.51570C>T - Protein change
- R505Q, R280Q
- Other names
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- Canonical SPDI
- NC_000005.10:74720647:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00003
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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. |
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HEXB | - | - |
GRCh38 GRCh37 |
794 | 818 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
no assertion criteria provided
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Sep 8, 1993 | RCV000004083.2 | |
Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000669552.15 |
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
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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. |
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Likely pathogenic
(Sep 22, 2017)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000794314.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Pathogenic
(Oct 18, 2020)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001442639.1
First in ClinVar: Nov 14, 2020 Last updated: Nov 14, 2020 |
Comment:
Variant summary: HEXB c.1514G>A (p.Arg505Gln) results in a conservative amino acid change located in the Glycoside hydroxylase family 20, catalytic domain (IPR015883) of the encoded … (more)
Variant summary: HEXB c.1514G>A (p.Arg505Gln) results in a conservative amino acid change located in the Glycoside hydroxylase family 20, catalytic domain (IPR015883) 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 3.2e-05 in 251186 control chromosomes. c.1514G>A has been reported in the literature in multiple individuals affected with adult and juvenile onset Sandhoff Disease (example, Redonnet-Vernhet_1996, Hara_1998, Sakuraba_2002, Utsumi_2002, Delnooz_2010, Clarke_2011, Gort_2012, Sobek_2012, Yasui_2013). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe impairment of normal enzyme activity (example, Redonnet-Vernhet_1996). 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Oct 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001391079.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 505 of the HEXB protein (p.Arg505Gln). … (more)
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 505 of the HEXB protein (p.Arg505Gln). This variant is present in population databases (rs121907983, gnomAD 0.01%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 8950198, 12027830, 23759947). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3879). 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: 8357844). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Aug 26, 2021)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002024988.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Feb 01, 2024)
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criteria provided, single submitter
Method: curation
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Sandhoff disease
Affected status: no
Allele origin:
germline
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Laboratory of Medical Genetics, National & Kapodistrian University of Athens
Accession: SCV005051826.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Pathogenic
(Sep 08, 1993)
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no assertion criteria provided
Method: literature only
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SANDHOFF DISEASE, ADULT TYPE
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024249.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In 2 sisters with adult Sandhoff disease (268800) presenting as spinocerebellar degeneration, reported by Oonk et al. (1979) and previously studied by Bolhuis et al. … (more)
In 2 sisters with adult Sandhoff disease (268800) presenting as spinocerebellar degeneration, reported by Oonk et al. (1979) and previously studied by Bolhuis et al. (1987), Bolhuis et al. (1993) found that the HEXB gene contained a G-to-A transition at nucleotide position 1514, resulting in a change in the electric charge at amino acid position 505 by substitution of glutamine for arginine in a highly conserved part of the beta chain. The nucleotide transition generated a new restriction site for DdeI, which was present in only 1 of the alleles. Bolhuis et al. (1993) demonstrated that the second allele was of mRNA-negative type. Thus, the patient was a genetic compound. (less)
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Pathogenic
(Sep 08, 2020)
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no assertion criteria provided
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002084952.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular pathology of Sandhoff disease with p.Arg505Gln in HEXB: application of simulation analysis. | Yasui N | Journal of human genetics | 2013 | PMID: 23759947 |
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 |
GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. | Gort L | Gene | 2012 | PMID: 22789865 |
An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants). | Clarke JT | Molecular genetics and metabolism | 2011 | PMID: 20926324 |
New cases of adult-onset Sandhoff disease with a cerebellar or lower motor neuron phenotype. | Delnooz CC | Journal of neurology, neurosurgery, and psychiatry | 2010 | PMID: 20798201 |
Molecular and structural studies of the GM2 gangliosidosis 0 variant. | Sakuraba H | Journal of human genetics | 2002 | PMID: 12166653 |
Western blotting analysis of the beta-hexosaminidase alpha- and beta-subunits in cultured fibroblasts from cases of various forms of GM2 gangliosidosis. | Utsumi K | Acta neurologica Scandinavica | 2002 | PMID: 12027830 |
Adult Sandhoff's disease: R505Q and I207V substitutions in the HEXB gene of the first Japanese case. | Hara A | Journal of the neurological sciences | 1998 | PMID: 9562328 |
Significance of two point mutations present in each HEXB allele of patients with adult GM2 gangliosidosis (Sandhoff disease) homozygosity for the Ile207-->Val substitution is not associated with a clinical or biochemical phenotype. | Redonnet-Vernhet I | Biochimica et biophysica acta | 1996 | PMID: 8950198 |
Molecular basis of an adult form of Sandhoff disease: substitution of glutamine for arginine at position 505 of the beta-chain of beta-hexosaminidase results in a labile enzyme. | Bolhuis PA | Biochimica et biophysica acta | 1993 | PMID: 8357844 |
Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease. | Bolhuis PA | Neurology | 1987 | PMID: 2948136 |
Spinocerebellar degeneration: hexosaminidase A and B deficiency in two adult sisters. | Oonk JG | Neurology | 1979 | PMID: 571983 |
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Text-mined citations for rs121907983 ...
HelpRecord 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.