Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). 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 (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. 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.1509-26G>A
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.
(10)
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
10
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.1509-26G>A
Variation ID: 527971 Accession: VCV000527971.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 5q13.3 5: 74720617 (GRCh38) [ NCBI UCSC ] 5: 74016442 (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 May 28, 2018 Oct 20, 2024 Mar 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000521.4:c.1509-26G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
intron variant NM_001292004.2:c.834-26G>A intron variant NC_000005.10:g.74720617G>A NC_000005.9:g.74016442G>A NG_009770.3:g.85596G>A NG_011531.1:g.51601C>T - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000005.10:74720616: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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cryptic splice acceptor activation; Variation Ontology [ VariO:0375]
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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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Trans-Omics for Precision Medicine (TOPMed) 0.00004
- 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 (6) |
criteria provided, multiple submitters, no conflicts
|
Dec 14, 2023 | RCV000633008.13 | |
| Pathogenic (1) |
no assertion criteria provided
|
Oct 15, 1990 | RCV002286417.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Aug 9, 2021 | RCV002529814.2 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 1, 2024 | RCV003153772.8 |
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
(Jan 24, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000789239.1
First in ClinVar: May 28, 2018 Last updated: May 28, 2018 |
|
|
|
Pathogenic
(Nov 12, 2018)
|
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: SCV000919510.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: … (more)
Variant summary: HEXB c.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). 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 (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Aug 25, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579770.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PS3_MOD, PM3, PS4_SUP, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
|
Pathogenic
(Mar 24, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002810292.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Mar 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV003842519.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in … (more)
Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201) (less)
|
|
|
Pathogenic
(Dec 14, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754219.6
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. … (more)
This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Aug 09, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003689621.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from … (more)
The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. (less)
|
|
|
Likely pathogenic
(Mar 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004811479.7
First in ClinVar: Apr 15, 2024 Last updated: Oct 20, 2024 |
Comment:
HEXB: PM2, PM3, PP3, PP4, PS3:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Oct 15, 1990)
|
no assertion criteria provided
Method: literature only
|
SANDHOFF DISEASE, JUVENILE TYPE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024245.1
First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013 |
Comment on evidence:
In a case of the juvenile form of Sandhoff disease (268800) reported by Wood and MacDougall (1976), Nakano and Suzuki (1989) showed that a cDNA … (more)
In a case of the juvenile form of Sandhoff disease (268800) reported by Wood and MacDougall (1976), Nakano and Suzuki (1989) showed that a cDNA clone isolated from fibroblasts contained an extra 24-base segment between exons 12 and 13. This segment was identified as the 3-prime terminus of intron 12. The remainder of the coding sequence was completely normal. The insertion was 'in frame' and added 8 amino acids between amino acids 491 and 492 of the enzyme protein. It was located only 5 amino acids away from a possible glycosylation site. Gene amplification by the PCR and subsequent sequencing of genomic DNA showed that the patient was a compound heterozygote. In 1 allele there was a single nucleotide transition from normal G to A at 26 bases from the 3-prime terminus of intron 12. This mutation generated a consensus sequence for the 3-prime splice site for an intron and thus explained the abnormal mRNAs that retain 24 bases of the 3-prime terminus of intron 12. The intron 12 and flanking exons 12 and 13 sequences were normal in the other allele. The other mutant allele was thought to be of an mRNA-negative type. The same mutation was found in a 35-year-old Japanese man with manifestations of juvenile Sandhoff disease: progressive neurogenic muscular atrophy, cerebellar ataxia, and mental deterioration beginning at age 10. Dlott et al. (1990) found the same mutation in cells from 2 juvenile Sandhoff disease patients and a third, asymptomatic individual. (less)
|
|
|
Pathogenic
(Dec 10, 2020)
|
no assertion criteria provided
Method: clinical testing
|
Sandhoff disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002084949.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201)
Comment:
This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
HEXB: PM2, PM3, PP3, PP4, PS3:Supporting
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.1509-26G>A is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 3 acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Nakano_1989). The variant allele was found at a frequency of 4.9e-05 in 245836 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXB causing Sandhoff Disease (4.9e-05 vs 0.0015), allowing no conclusion about variant significance. The variant, c.1509-26G>A, has been reported in the literature in multiple individuals affected with Sandhoff Disease, homozygotes and compound heterozygotes (Delnooz_2009, Gort_2012). 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 (Delnooz_2009). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic and uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Published functional studies demonstrate a damaging effect resulting from abnormal splicing and a longer protein (Nakano et al., 1989); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as IVS12-26; This variant is associated with the following publications: (PMID: 23046579, 2522450, 24915922, 17015493, 22789865, 2147031, 2170400, 1386607, 2147027, 27021291, 20798201)
Comment:
This sequence change falls in intron 12 of the HEXB gene. It does not directly change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and likely results in the gain of 8 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs201580118, gnomAD 0.01%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 2522450, 17015493, 22789865, 24915922; Invitae). ClinVar contains an entry for this variant (Variation ID: 527971). Studies have shown that this variant results in the activation of a cryptic splice site in intron 12 (PMID: 2522450). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.1509-26G>A intronic alteration results from a G to A substitution 26 nucleotides before coding exon 13 of the HEXB gene. Based on data from gnomAD, the A allele has an overall frequency of <0.01% (12/250940) total alleles studied. The highest observed frequency was 0.01% (12/113452) of European (non-Finnish) alleles. This alteration has been reported in association with Sandhoff disease in homozygotes and in heterozygotes with an additional HEXB variant (Maegawa, 2006; Delnooz, 2010; Gort, 2012; Zhang 2016). Experimental evidence suggests this alteration has an impact on splicing resulting in an in-frame insertion of 24 nucleotides and 8 amino acids (Nakano, 1989). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic.
Comment:
HEXB: PM2, PM3, PP3, PP4, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Clinical,biochemical and molecular analysis of five Chinese patients with Sandhoff disease. | Zhang W | Metabolic brain disease | 2016 | PMID: 27021291 |
| [Clinical and molecular characteristics of a child with juvenile Sandhoff disease]. | Huang Y | Zhonghua er ke za zhi = Chinese journal of pediatrics | 2014 | PMID: 24915922 |
| 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 |
| 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 |
| The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. | Maegawa GH | Pediatrics | 2006 | PMID: 17015493 |
| Two mutations produce intron insertion in mRNA and elongated beta-subunit of human beta-hexosaminidase. | Dlott B | The Journal of biological chemistry | 1990 | PMID: 2170400 |
| Juvenile Sandhoff disease: a Japanese patient carrying a mutation identical to that found earlier in a Canadian patient. | Mitsuo K | Journal of the neurological sciences | 1990 | PMID: 2147031 |
| Genetic cause of a juvenile form of Sandhoff disease. Abnormal splicing of beta-hexosaminidase beta chain gene transcript due to a point mutation within intron 12. | Nakano T | The Journal of biological chemistry | 1989 | PMID: 2522450 |
| Juvenile Sandhoff disease: some properties of the residual hexosaminidase in cultured fibroblasts. | Wood S | American journal of human genetics | 1976 | PMID: 10724 |
Text-mined citations for rs201580118 ...
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 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.