ClinVar Genomic variation as it relates to human health
NM_000521.4(HEXB):c.1597C>T (p.Arg533Cys)
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.1597C>T (p.Arg533Cys)
Variation ID: 435415 Accession: VCV000435415.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.3 5: 74720731 (GRCh38) [ NCBI UCSC ] 5: 74016556 (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 Aug 28, 2017 Feb 14, 2024 Jan 18, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000521.4:c.1597C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000512.2:p.Arg533Cys missense NM_001292004.2:c.922C>T NP_001278933.1:p.Arg308Cys missense NC_000005.10:g.74720731C>T NC_000005.9:g.74016556C>T NG_009770.2:g.85709C>T NG_011531.1:g.51487G>A - Protein change
- R533C, R308C
- Other names
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- Canonical SPDI
- NC_000005.10:74720730:C:T
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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.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD), exomes 0.00003
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 | ||
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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
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
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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 (10) |
criteria provided, multiple submitters, no conflicts
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Jan 18, 2024 | RCV000502357.24 |
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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Pathogenic
(Apr 19, 2016)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000595122.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Oct 26, 2018)
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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: SCV000919509.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: HEXB c.1597C>T (p.Arg533Cys) 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.1597C>T (p.Arg533Cys) 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 allele was found at a frequency of 3.2e-05 in 246212 control chromosomes (gnomAD and publication). c.1597C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Sandhoff Disease with limited or absent Hex activity (Gort_2012, Aryan_2012, Kaya_2011, Zampieri_2012). These data indicate that the variant is very likely to be associated with disease. Two CllinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: yes
Allele origin:
germline
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Centogene AG - the Rare Disease Company
Accession: SCV001424439.1
First in ClinVar: Jul 25, 2020 Last updated: Jul 25, 2020 |
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Pathogenic
(Mar 16, 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: SCV002024990.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 18, 2024)
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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: SCV001228728.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 533 of the HEXB protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 533 of the HEXB protein (p.Arg533Cys). This variant is present in population databases (rs764552042, gnomAD 0.006%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 21567908, 22848519, 23010210, 27682710). ClinVar contains an entry for this variant (Variation ID: 435415). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXB function (PMID: 22848519). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 04, 2022)
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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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Fulgent Genetics, Fulgent Genetics
Accession: SCV002801454.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: yes
Allele origin:
germline
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Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV002820229.1
First in ClinVar: Jan 21, 2023 Last updated: Jan 21, 2023 |
Comment:
The missense variant p.R533C in HEXB (NM_000521.3) has been previously reported in affected patients including thosefrom Indian origin (Tamhankar et al, 2016).It has been reported … (more)
The missense variant p.R533C in HEXB (NM_000521.3) has been previously reported in affected patients including thosefrom Indian origin (Tamhankar et al, 2016).It has been reported in the ClinVar database as a Pathogenic variant.The p.R533C variant is observed in 2/30,604(0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in1000 Genomes.There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties.The p.R533C missense variant is predicted to be damaging by both SIFT and PolyPhen2.The arginine residue at codon 533 of HEXB is conserved in all mammalian species.The nucleotide c.1597 in HEXB is predicted conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Growth delay (present) , Seizure (present)
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Likely pathogenic
(Jan 30, 2018)
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no assertion criteria provided
Method: clinical testing
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Sandhoff disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000797401.2
First in ClinVar: Aug 28, 2017 Last updated: Dec 23, 2019 |
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Pathogenic
(Sep 16, 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: SCV001457618.1
First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021 |
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Pathogenic
(Sep 10, 2020)
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no assertion criteria provided
Method: clinical testing
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Sandhoff disease
Affected status: yes
Allele origin:
germline
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Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City
Accession: SCV001469235.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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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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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 |
Clinical, biochemical and mutation profile in Indian patients with Sandhoff disease. | Tamhankar PM | Journal of human genetics | 2016 | PMID: 26582265 |
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 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay-Sachs and 14 Sandhoff patients. | Gort L | Gene | 2012 | PMID: 22789865 |
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 |
Text-mined citations for rs764552042 ...
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.