ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.1177C>T (p.Arg393Ter)
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.1177C>T (p.Arg393Ter)
Variation ID: 3905 Accession: VCV000003905.94
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 72346680 (GRCh38) [ NCBI UCSC ] 15: 72639021 (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 May 1, 2024 Nov 16, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000520.6:c.1177C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Arg393Ter nonsense NM_001318825.2:c.1210C>T NP_001305754.1:p.Arg404Ter nonsense NC_000015.10:g.72346680G>A NC_000015.9:g.72639021G>A NG_009017.2:g.34500C>T - Protein change
- R393*, R404*
- Other names
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- Canonical SPDI
- NC_000015.10:72346679:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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 (6) |
criteria provided, multiple submitters, no conflicts
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Nov 16, 2023 | RCV000004111.85 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 20, 2017 | RCV000522695.7 |
Submissions - Germline
Classification
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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
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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
(Oct 20, 2017)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000617693.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The R393X variant in the HEXA gene has been reported previously in association with infantile Tay-Sachs disease (Akli et al., 1991; Ozkara et al., 1998; … (more)
The R393X variant in the HEXA gene has been reported previously in association with infantile Tay-Sachs disease (Akli et al., 1991; Ozkara et al., 1998; Haghighi et al., 2011). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R393X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R393X as a pathogenic variant. (less)
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Pathogenic
(Feb 22, 2021)
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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: SCV001482257.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
Variant summary: HEXA c.1177C>T (p.Arg393X) 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.1177C>T (p.Arg393X) 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. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). c.1177C>T has been reported in the literature in multiple individuals (including several homozygous patients) affected with Tay-Sachs Disease (example: Akli_1991, Jamali_2014, Naseer_2020). These data indicate that the variant is very likely to be associated with disease. Akli et al report that northern blot analysis of fibroblasts derived from a patient homozygous for the variant showed no detectable level of mRNA (Akli_1991). Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Feb 13, 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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Revvity Omics, Revvity
Accession: SCV002024985.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 16, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000955425.4
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg393*) 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.Arg393*) 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). This variant is present in population databases (rs121907963, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with hexosaminidase A deficiency (PMID: 1837283, 21796138, 24518553, 32968423). ClinVar contains an entry for this variant (Variation ID: 3905). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Apr 22, 2015)
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no assertion criteria provided
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV001132224.1
First in ClinVar: Dec 23, 2019 Last updated: Dec 23, 2019 |
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Affects
(Sep 01, 1991)
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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
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OMIM
Accession: SCV000024277.64
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a nonsense mutation in exon 11 that converted arginine-393 to stop. Both … (more)
Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a nonsense mutation in exon 11 that converted arginine-393 to stop. Both this and the arg137-to-ter mutation were associated with a marked decrease in the abundance of mRNA, probably because they resulted in mRNA instability. (less)
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Pathogenic
(Mar 17, 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: SCV002085677.1
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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Whole exome sequencing reveals a homozygous nonsense mutation in HEXA gene leading to Tay-Sachs disease in Saudi Family. | Naseer MI | Pakistan journal of medical sciences | 2020 | PMID: 32968423 |
Three novel mutations in Iranian patients with Tay-Sachs disease. | Jamali S | Iranian biomedical journal | 2014 | PMID: 24518553 |
Identification of two HEXA mutations causing infantile-onset Tay-Sachs disease in the Persian population. | Haghighi A | Journal of human genetics | 2011 | PMID: 21796138 |
Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments. | Akli S | Genomics | 1991 | PMID: 1837283 |
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 rs121907963 ...
HelpRecord 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.