ClinVar Genomic variation as it relates to human health
NM_000521.4(HEXB):c.1627G>A (p.Ala543Thr)
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.1627G>A (p.Ala543Thr)
Variation ID: 3881 Accession: VCV000003881.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q13.3 5: 74721131 (GRCh38) [ NCBI UCSC ] 5: 74016956 (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 Feb 14, 2024 Jan 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000521.4:c.1627G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000512.2:p.Ala543Thr missense NM_001292004.2:c.952G>A NP_001278933.1:p.Ala318Thr missense NC_000005.10:g.74721131G>A NC_000005.9:g.74016956G>A NG_009770.2:g.86109G>A NG_011531.1:g.51087C>T NP_000512.1:p.Ala543Thr - Protein change
- A543T, A318T
- Other names
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- Canonical SPDI
- NC_000005.10:74721130: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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0.00060 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00011
The Genome Aggregation Database (gnomAD) 0.00012
1000 Genomes Project 30x 0.00047
1000 Genomes Project 0.00060
The Genome Aggregation Database (gnomAD), exomes 0.00086
Exome Aggregation Consortium (ExAC) 0.00095
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
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. |
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HEXB | - | - |
GRCh38 GRCh37 |
783 | 807 |
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. |
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Benign (1) |
no assertion criteria provided
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Jan 1, 1997 | RCV000004085.3 | |
Likely benign; other (2) |
criteria provided, multiple submitters, no conflicts
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Oct 31, 2016 | RCV000079061.11 | |
Likely benign (5) |
criteria provided, multiple submitters, no conflicts
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Jan 21, 2024 | RCV000987527.15 |
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
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. |
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Likely benign
(Oct 31, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000697176.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The … (more)
Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 115/120804 (1/1052, 1 homozygote), predominantly observed in the South Asian cohort, 92/16490 (1/179, 1 homozygote), which exceeds the estimated maximal expected allele frequency for a pathogenic HEXB variant of 1/676. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has been reported in multiple affected and healthy homozygous individuals via publications. Functional studies have shown that the variant of interest is a heat labile allele, meaning that it leads to reduction in enzyme activity and mightresult in a false non-TSD or non-SD diagnosis. Likewise, a doubly heterozygous person, for TSD and for HLB, could be misdiagnosed as a normal homozygote. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign," along with the reporting cautionary awareness for the heat labile aspect. Therefore, to indicate the potential for the variant to cause false negative results, a classification of "Probable Normal Variant/Likely Benign," has been assigned to this variant. (less)
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other
(Dec 18, 2012)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000110930.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 06, 2016 |
Number of individuals with the variant: 3
Sex: mixed
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Likely benign
(May 28, 2019)
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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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Mendelics
Accession: SCV001136840.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely benign
(Jan 18, 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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Illumina Laboratory Services, Illumina
Accession: SCV001315843.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Sandhoff disease
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440662.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely benign
(Jan 21, 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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Invitae
Accession: SCV001055645.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024 |
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Benign
(Jan 01, 1997)
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no assertion criteria provided
Method: literature only
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HEXOSAMINIDASE B, HEAT-LABILE POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000024251.2
First in ClinVar: Apr 04, 2013 Last updated: May 04, 2020 |
Comment on evidence:
Genotyping individuals for Tay-Sachs disease (TSD) (272800) is based mainly on the heat lability of beta-hexosaminidase (Hex) A (606869) and the heat stability of Hex … (more)
Genotyping individuals for Tay-Sachs disease (TSD) (272800) is based mainly on the heat lability of beta-hexosaminidase (Hex) A (606869) and the heat stability of Hex B. Mutations in the HEXB gene encoding the beta subunits of Hex that result in heat-labile hexosaminidase B thus may lead to erroneous enzymatic genotyping regarding TSD. Using single strand conformation polymorphism (SSCP) analysis for all 14 exons of HEXB followed by direct sequencing of aberrant fragments, Narkis et al. (1997) screened individuals whose Hex B was heat labile. These were Jewish and Arab individuals that had been identified by Navon and Adam (1990) and by Navon et al. (1985). The heat-labile mutation in these instances was identified as 1627 G-A. This caused an ala543-to-thr substitution in the beta-subunit protein. One individual with heat-labile Hex B was negative for the 1627 G-A mutation, as well as for the heat-labile mutation 1514 G-A (606873.0009), proving that there exists at least one other heat-labile Hex B mutation. (less)
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Benign
(Jan 09, 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: SCV002084958.1
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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Personalized genomic disease risk of volunteers. | Gonzalez-Garay ML | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 24082139 |
Loss of protein structure stability as a major causative factor in monogenic disease. | Yue P | Journal of molecular biology | 2005 | PMID: 16169011 |
The X-ray crystal structure of human beta-hexosaminidase B provides new insights into Sandhoff disease. | Maier T | Journal of molecular biology | 2003 | PMID: 12706724 |
Molecular basis of heat labile hexosaminidase B among Jews and Arabs. | Narkis G | Human mutation | 1997 | PMID: 9401004 |
Substitution of alanine543 with a threonine residue at the carboxy terminal end of the beta-chain is associated with thermolabile hexosaminidase B in a Jewish family of Oriental ancestry. | De Gasperi R | Biochemical and molecular medicine | 1995 | PMID: 8593535 |
Thermolabile hexosaminidase (Hex) B: diverse frequencies among Jewish communities and implication for screening of sera for Hex A deficiencies. | Navon R | Human heredity | 1990 | PMID: 2139865 |
Hereditary heat-labile hexosaminidase B: a variant whose homozygotes synthesize a functional HEX A. | Navon R | American journal of human genetics | 1985 | PMID: 3156493 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXB | - | - | - | - |
Text-mined citations for rs121907984 ...
HelpRecord last updated Feb 20, 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.