This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs121907980, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1483696, 22789865). It is commonly reported in individuals of French Canadian ancestry (PMID: 1483696). This variant is also known as IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 3938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.805+1G>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.
(7)
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
7
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000520.6(HEXA):c.805+1G>A
Variation ID: 3938 Accession: VCV000003938.105
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 72350517 (GRCh38) [ NCBI UCSC ] 15: 72642858 (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 Oct 8, 2024 Nov 27, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000520.6:c.805+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000520.5:c.805+1G>A NM_001318825.2:c.838+1G>A splice donor NC_000015.10:g.72350517C>T NC_000015.9:g.72642858C>T NG_009017.2:g.30663G>A NG_009017.3:g.30497G>A - Protein change
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- Other names
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IVS7, G-A, +1
- Canonical SPDI
- NC_000015.10:72350516: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
Help
The frequency of the allele represented by this VCV record.
- -
- 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. |
|||
| HEXA | - | - |
GRCh38 GRCh37 |
1141 | 1175 | |
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 (6) |
criteria provided, multiple submitters, no conflicts
|
Nov 27, 2023 | RCV000409276.82 | |
|
HEXA-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Feb 9, 2024 | RCV003944800.2 |
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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|---|---|---|---|---|---|
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Pathogenic
(Nov 27, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000933483.5
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt … (more)
This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs121907980, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1483696, 22789865). It is commonly reported in individuals of French Canadian ancestry (PMID: 1483696). This variant is also known as IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 3938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 14, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919501.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal … (more)
Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which is supported by a functional study (Hechtman_1992). In addition, Gort_2012 observed very little (<10%) HEXA activity in a compound heterozygote affected individual. This variant was found in 1/246234 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly French Canadians. In addition, a clinical diagnostic laboratory and reputable database classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
|
Pathogenic
(Nov 12, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001193926.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with Tay-Sachs disease. Sources cited for classification include the … (more)
NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 22789865, 1483696 and 7717398. Classification of NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
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Pathogenic
(May 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002811013.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
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Affects
(Dec 01, 1992)
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no assertion criteria provided
Method: literature only
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TAY-SACHS DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024309.64
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
Hechtman et al. (1992) found a second mutation as the cause of infantile Tay-Sachs disease (272800) in French Canadians in 3 families from the Saguenay-Lac-Saint-Jean … (more)
Hechtman et al. (1992) found a second mutation as the cause of infantile Tay-Sachs disease (272800) in French Canadians in 3 families from the Saguenay-Lac-Saint-Jean region of Quebec: a G-to-A transition at the +1 position of intron 7 that abolished the donor splice site. The mutation occurred in a base adjacent to the site. (less)
|
|
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Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002086283.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
|
|
Pathogenic
(Feb 09, 2024)
|
no assertion criteria provided
Method: clinical testing
|
HEXA-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004759685.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The HEXA c.805+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous … (more)
The HEXA c.805+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in multiple individuals with Tay-Sachs disease and was also shown to segregate with disease in three unrelated families (Figure 2, Hechtman et al. 1992. PubMed ID: 1483696; Table 2, Triggs-Raine et al. 1995. PubMed ID: 7717398; Table 1, Gort et al. 2012. PubMed ID: 22789865). Experimental studies suggest this variant impacts protein function showing little to no HexA activity in both serum and cultured human fibroblasts of the affected probands (Hechtman et al. 1992. PubMed ID: 1483696; Gort et al. 2012. PubMed ID: 22789865). This variant was found frequently in individuals of French Canadian ancestry (Hechtman et al. 1992. PubMed ID: 1483696). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in HEXA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. (less)
|
Comment:
Comment:
Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which is supported by a functional study (Hechtman_1992). In addition, Gort_2012 observed very little (<10%) HEXA activity in a compound heterozygote affected individual. This variant was found in 1/246234 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly French Canadians. In addition, a clinical diagnostic laboratory and reputable database classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 22789865, 1483696 and 7717398. Classification of NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The HEXA c.805+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in multiple individuals with Tay-Sachs disease and was also shown to segregate with disease in three unrelated families (Figure 2, Hechtman et al. 1992. PubMed ID: 1483696; Table 2, Triggs-Raine et al. 1995. PubMed ID: 7717398; Table 1, Gort et al. 2012. PubMed ID: 22789865). Experimental studies suggest this variant impacts protein function showing little to no HexA activity in both serum and cultured human fibroblasts of the affected probands (Hechtman et al. 1992. PubMed ID: 1483696; Gort et al. 2012. PubMed ID: 22789865). This variant was found frequently in individuals of French Canadian ancestry (Hechtman et al. 1992. PubMed ID: 1483696). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in HEXA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.
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:
This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs121907980, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1483696, 22789865). It is commonly reported in individuals of French Canadian ancestry (PMID: 1483696). This variant is also known as IVS7+1G>A. ClinVar contains an entry for this variant (Variation ID: 3938). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Comment:
Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which is supported by a functional study (Hechtman_1992). In addition, Gort_2012 observed very little (<10%) HEXA activity in a compound heterozygote affected individual. This variant was found in 1/246234 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly French Canadians. In addition, a clinical diagnostic laboratory and reputable database classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency and is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 22789865, 1483696 and 7717398. Classification of NM_000520.4(HEXA):c.805+1G>A(aka IVS7+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The HEXA c.805+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was reported in the compound heterozygous state in multiple individuals with Tay-Sachs disease and was also shown to segregate with disease in three unrelated families (Figure 2, Hechtman et al. 1992. PubMed ID: 1483696; Table 2, Triggs-Raine et al. 1995. PubMed ID: 7717398; Table 1, Gort et al. 2012. PubMed ID: 22789865). Experimental studies suggest this variant impacts protein function showing little to no HexA activity in both serum and cultured human fibroblasts of the affected probands (Hechtman et al. 1992. PubMed ID: 1483696; Gort et al. 2012. PubMed ID: 22789865). This variant was found frequently in individuals of French Canadian ancestry (Hechtman et al. 1992. PubMed ID: 1483696). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in HEXA are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of French Canadian background living in New England. | Triggs-Raine B | American journal of human genetics | 1995 | PMID: 7717398 |
| Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
| The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada. | Hechtman P | Human genetics | 1992 | PMID: 1483696 |
| Sequence of DNA flanking the exons of the HEXA gene, and identification of mutations in Tay-Sachs disease. | Triggs-Raine BL | American journal of human genetics | 1991 | PMID: 1833974 |
Text-mined citations for rs121907980 ...
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 Nov 10, 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.