Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.1421+1G>C
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
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_000520.6(HEXA):c.1421+1G>C
Variation ID: 3890 Accession: VCV000003890.104
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q23 15: 72346234 (GRCh38) [ NCBI UCSC ] 15: 72638575 (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 Oct 9, 2016 May 1, 2024 Jan 19, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000520.6:c.1421+1G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_000520.5:c.1421+1G>C NM_001318825.2:c.1454+1G>C splice donor NC_000015.10:g.72346234C>G NC_000015.9:g.72638575C>G NG_009017.2:g.34946G>C NG_009017.3:g.34780G>C - Protein change
- -
- Other names
-
IVS12, G-C, +1
- Canonical SPDI
- NC_000015.10:72346233:C:G
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
The Genome Aggregation Database (gnomAD) 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00005
Exome Aggregation Consortium (ExAC) 0.00009
The Genome Aggregation Database (gnomAD), exomes 0.00012
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- 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 (8) |
criteria provided, multiple submitters, no conflicts
|
Jan 19, 2024 | RCV000004094.90 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Oct 23, 2023 | RCV000255737.10 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Jan 19, 2016)
|
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: SCV000697163.1
First in ClinVar: Jul 08, 2017 Last updated: Jul 08, 2017 |
Comment:
Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict … (more)
Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic. (less)
|
|
|
Pathogenic
(Dec 19, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194175.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification … (more)
NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C 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)
|
|
|
Pathogenic
(Apr 26, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322422.6
First in ClinVar: Oct 09, 2016 Last updated: Apr 17, 2019 |
Comment:
Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice … (more)
Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988); Kaback, M. and Desnick, R. (Updated [August 11, 2011]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2015. Available at http://www.genetests.org. Accessed [Nov 2016]; Ohno et al. (1988) Biochem. Biophys. Res. Commun. 153 (1):463-9 (PMID: 2837213);; This variant is associated with the following publications: (PMID: 3362213, 25525159, 22975760, 2837213, 9222766, 2973464, 3375249, 22109873, 29795570, 16088929, 8490625, 1833974, 1387685) (less)
|
|
|
Pathogenic
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
germline
|
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002768361.1
First in ClinVar: Dec 24, 2022 Last updated: Dec 24, 2022 |
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism … (more)
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RNA studies showed intron 12 retention. However, the authors were unable to predict whether the entire intron or only part of it was retained (PMID: 2837213). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar, PMIDs: 2837213, 23852624). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
|
|
|
Pathogenic
(Jan 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000894056.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Oct 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV004564025.1
First in ClinVar: Feb 20, 2024 Last updated: Feb 20, 2024 |
Comment:
The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected … (more)
The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected with Tay-Sachs disease (Arpaia 1988, Kaufman 1997). This variant is also reported in ClinVar (Variation ID: 3890), and is found in the Ashkenazi Jewish population with an allele frequency of 0.25% (25/10032 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function Based on available information, this variant is considered to be pathogenic. References: Arpaia E et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85-6. Kaufman M et al. Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat. 1997;10(4):295-300. (less)
|
|
|
Pathogenic
(Jun 11, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV002024980.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Jan 19, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000931129.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024 |
Comment:
This sequence change affects a donor splice site in intron 12 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 12 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 (rs147324677, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 2837213, 2973464, 3362213, 3375249, 9222766). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 16088929). This variant is also known as IVS12+1G>C. ClinVar contains an entry for this variant (Variation ID: 3890). 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)
|
|
|
Affects
(Jan 01, 1997)
|
no assertion criteria provided
Method: literature only
|
TAY-SACHS DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024260.66
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
Arpaia et al. (1988) identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease (272800). … (more)
Arpaia et al. (1988) identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease (272800). The change, a G-to-C substitution in the first nucleotide of intron 12, was expected to result in defective splicing of the mRNA. A test for the mutant allele based on amplification of DNA by the PCR and cleavage of a DdeI restriction site generated by the mutation showed that this case and 2 other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for 2 different mutations. The mutation was found in over 20% of the Tay-Sachs alleles that they examined in Ashkenazi Jewish patients and carriers but in none of 43 normal Jewish persons. Arpaia et al. (1988) suggested that the occurrence of multiple mutant alleles in Ashkenazim warrants further examination of the selective advantage hypothesis; the hypothesis of founder effect suggests the existence of a single mutant allele. In a case of classic infantile Tay-Sachs disease in an Ashkenazi Jewish patient, Ohno and Suzuki (1988) found that there were 2 types of Hex-A mRNA: intact mRNA and mRNA with truncated intron 12 sequences. Sequence analysis showed a single G-to-C nucleotide transversion at the 5-prime donor site of intron 12, the same change as that in the patient of Arpaia et al. (1988). Both patients were compound heterozygotes. Myerowitz (1988) likewise found in each of 2 unrelated Ashkenazi patients that 1 alpha-chain allele harbored the splice junction mutation. Only 1 parent of each of these patients was positive for the defect. Thirty percent of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. In an Ashkenazi Jewish child with Tay-Sachs disease and a splicing defect at the 5-prime donor site of intron 12, present in heterozygous state, Ohno and Suzuki (1988) found a variety of abnormal mRNAs. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 13% of cases in this ethnic group. Strasberg et al. (1997) reported the first incidence of homozygosity for the intron 12 mutation in a female infant with classic TSD. The child first presented at the age of 13.5 months with seizures associated with fever and pneumococcal bacteremia. Developmental delay had been recognized from early in life with no history of regression or exaggerated startle reflex. At 13 months, she showed central hypotonia and peripheral hypertonia with exaggerated deep tendon reflexes and bilateral ankle clonus. Funduscopy revealed bilateral cherry red spots of the macula. (less)
|
|
|
Pathogenic
(Mar 17, 2017)
|
no assertion criteria provided
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Natera, Inc.
Accession: SCV002085664.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C 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:
Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988); Kaback, M. and Desnick, R. (Updated [August 11, 2011]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2015. Available at http://www.genetests.org. Accessed [Nov 2016]; Ohno et al. (1988) Biochem. Biophys. Res. Commun. 153 (1):463-9 (PMID: 2837213);; This variant is associated with the following publications: (PMID: 3362213, 25525159, 22975760, 2837213, 9222766, 2973464, 3375249, 22109873, 29795570, 16088929, 8490625, 1833974, 1387685)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RNA studies showed intron 12 retention. However, the authors were unable to predict whether the entire intron or only part of it was retained (PMID: 2837213). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar, PMIDs: 2837213, 23852624). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected with Tay-Sachs disease (Arpaia 1988, Kaufman 1997). This variant is also reported in ClinVar (Variation ID: 3890), and is found in the Ashkenazi Jewish population with an allele frequency of 0.25% (25/10032 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function Based on available information, this variant is considered to be pathogenic. References: Arpaia E et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85-6. Kaufman M et al. Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat. 1997;10(4):295-300.
Comment:
This sequence change affects a donor splice site in intron 12 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 (rs147324677, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 2837213, 2973464, 3362213, 3375249, 9222766). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 16088929). This variant is also known as IVS12+1G>C. ClinVar contains an entry for this variant (Variation ID: 3890). 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.
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: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic.
Comment:
NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C 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:
Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988); Kaback, M. and Desnick, R. (Updated [August 11, 2011]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2015. Available at http://www.genetests.org. Accessed [Nov 2016]; Ohno et al. (1988) Biochem. Biophys. Res. Commun. 153 (1):463-9 (PMID: 2837213);; This variant is associated with the following publications: (PMID: 3362213, 25525159, 22975760, 2837213, 9222766, 2973464, 3375249, 22109873, 29795570, 16088929, 8490625, 1833974, 1387685)
Comment:
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RNA studies showed intron 12 retention. However, the authors were unable to predict whether the entire intron or only part of it was retained (PMID: 2837213). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar, PMIDs: 2837213, 23852624). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Comment:
The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected with Tay-Sachs disease (Arpaia 1988, Kaufman 1997). This variant is also reported in ClinVar (Variation ID: 3890), and is found in the Ashkenazi Jewish population with an allele frequency of 0.25% (25/10032 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function Based on available information, this variant is considered to be pathogenic. References: Arpaia E et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85-6. Kaufman M et al. Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat. 1997;10(4):295-300.
Comment:
This sequence change affects a donor splice site in intron 12 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 (rs147324677, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 2837213, 2973464, 3362213, 3375249, 9222766). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 16088929). This variant is also known as IVS12+1G>C. ClinVar contains an entry for this variant (Variation ID: 3890). 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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Burden of lysosomal storage disorders in India: experience of 387 affected children from a single diagnostic facility. | Sheth J | JIMD reports | 2014 | PMID: 23852624 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles. | Montalvo AL | Human mutation | 2005 | PMID: 16088929 |
| Homozygosity for the common Ashkenazi jewish Tay-Sachs +1 IVS-12 splice-junction mutation: first report. | Strasberg P | Human mutation | 1997 | PMID: 9222766 |
| Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
| 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 |
| Splice junction mutation in some Ashkenazi Jews with Tay-Sachs disease: evidence against a single defect within this ethnic group. | Myerowitz R | Proceedings of the National Academy of Sciences of the United States of America | 1988 | PMID: 3375249 |
| Identification of an altered splice site in Ashkenazi Tay-Sachs disease. | Arpaia E | Nature | 1988 | PMID: 3362213 |
| Multiple abnormal beta-hexosaminidase alpha chain mRNAs in a compound-heterozygous Ashkenazi Jewish patient with Tay-Sachs disease. | Ohno K | The Journal of biological chemistry | 1988 | PMID: 2973464 |
| The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. | Myerowitz R | The Journal of biological chemistry | 1988 | PMID: 2848800 |
| A splicing defect due to an exon-intron junctional mutation results in abnormal beta-hexosaminidase alpha chain mRNAs in Ashkenazi Jewish patients with Tay-Sachs disease. | Ohno K | Biochemical and biophysical research communications | 1988 | PMID: 2837213 |
| click to load more click to collapse | ||||
Text-mined citations for rs147324677 ...
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 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.