ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.1123del (p.Glu375fs)
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_000520.6(HEXA):c.1123del (p.Glu375fs)
Variation ID: 189166 Accession: VCV000189166.16
- Type and length
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Deletion, 1 bp
- Location
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Cytogenetic: 15q23 15: 72347709 (GRCh38) [ NCBI UCSC ] 15: 72640050 (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 Mar 29, 2015 Feb 14, 2024 Nov 6, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000520.6:c.1123del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Glu375fs frameshift NM_000520.4:c.1123del NM_001318825.2:c.1156del NP_001305754.1:p.Glu386fs frameshift NC_000015.10:g.72347710del NC_000015.9:g.72640051del NG_009017.2:g.33471del - Protein change
- E375fs, E386fs
- Other names
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- Canonical SPDI
- NC_000015.10:72347708:CC:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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HEXA | - | - |
GRCh38 GRCh37 |
1139 | 1173 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (6) |
criteria provided, multiple submitters, no conflicts
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Nov 6, 2023 | RCV000169594.13 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 4, 2023 | RCV001268863.3 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
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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
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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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Nov 25, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001362846.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HEXA c.1123delG (p.Glu375ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: HEXA c.1123delG (p.Glu375ArgfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.1e-06 in 246288 control chromosomes. c.1123delG has been reported in the literature in individuals affected with Tay-Sachs Disease (example, Montalvo_2005, Jamrozik_2013, Jahnova_2019). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function were ascertained in the context of this evaluation. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Apr 04, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004219901.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This frameshift variant alters the translational reading frame of the HEXA mRNA and causes the premature termination of HEXA protein synthesis. In the published literature, … (more)
This frameshift variant alters the translational reading frame of the HEXA mRNA and causes the premature termination of HEXA protein synthesis. In the published literature, the variant has been reported as compound heterozygous with other pathogenic variants in individuals with Tay-Sachs Disease (PMIDs: 16088929 (2005), 23820084 (2013), and 31076878 (2019)). Based on the available information, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440216.1
First in ClinVar: Oct 30, 2020 Last updated: Oct 30, 2020 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001448073.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Dysarthria (present) , Progressive cerebellar ataxia (present) , Dysphagia (present)
Sex: female
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Pathogenic
(Feb 09, 2022)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580325.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PVS1, PS4_MOD, PM3, PM2_SUP
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Number of individuals with the variant: 1
Sex: male
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Likely pathogenic
(Jan 30, 2015)
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criteria provided, single submitter
Method: literature only
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Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000221104.2
First in ClinVar: Mar 29, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Nov 06, 2023)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001204958.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Glu375Argfs*7) in the HEXA gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Glu375Argfs*7) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 16088929, 31076878). ClinVar contains an entry for this variant (Variation ID: 189166). 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)
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Pathogenic
(Mar 16, 2017)
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no assertion criteria provided
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002085680.1
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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Amyotrophy, cerebellar impairment and psychiatric disease are the main symptoms in a cohort of 14 Czech patients with the late-onset form of Tay-Sachs disease. | Jahnová H | Journal of neurology | 2019 | PMID: 31076878 |
Late onset GM2 gangliosidosis mimicking spinal muscular atrophy. | Jamrozik Z | Gene | 2013 | PMID: 23820084 |
Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis. | Lemieux MJ | Journal of molecular biology | 2006 | PMID: 16698036 |
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 |
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 |
Text-mined citations for rs766138785 ...
HelpRecord last updated Jun 23, 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.