The R137X pathogenic variant in the HEXA gene has been reported previously in association with Tay Sachs disease (Akli et al., 1991; Mules et al., 1992). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R137X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R137X as a pathogenic variant.
ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.409C>T (p.Arg137Ter)
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.
(8)
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
8
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.409C>T (p.Arg137Ter)
Variation ID: 3904 Accession: VCV000003904.94
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 72355562 (GRCh38) [ NCBI UCSC ] 15: 72647903 (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 Dec 23, 2023 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000520.6:c.409C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Arg137Ter nonsense NM_001318825.2:c.442C>T NP_001305754.1:p.Arg148Ter nonsense NR_134869.3:n.451C>T non-coding transcript variant NC_000015.10:g.72355562G>A NC_000015.9:g.72647903G>A NG_009017.2:g.25618C>T - Protein change
- R137*, R148*
- Other names
- -
- Canonical SPDI
- NC_000015.10:72355561: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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
Exome Aggregation Consortium (ExAC) 0.00002
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 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. |
|||
| 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
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Dec 23, 2023 | RCV000004110.88 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Apr 27, 2016 | RCV000255817.11 |
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
(Apr 27, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000322431.7
First in ClinVar: Oct 10, 2016 Last updated: Dec 15, 2018 |
Comment:
The R137X pathogenic variant in the HEXA gene has been reported previously in association with Tay Sachs disease (Akli et al., 1991; Mules et al., … (more)
The R137X pathogenic variant in the HEXA gene has been reported previously in association with Tay Sachs disease (Akli et al., 1991; Mules et al., 1992). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R137X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R137X as a pathogenic variant. (less)
|
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Pathogenic
(Jul 23, 2018)
|
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: SCV000917518.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: HEXA c.409C>T (p.Arg137X) 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.409C>T (p.Arg137X) 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 2.9e-05 in 277008 control chromosomes. c.409C>T has been reported in the literature in individuals affected with Tay-Sachs Disease (Gort_2012, Mules_1992, Ozkara_1998, Zampieri_2012). These data indicate that the variant is associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
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Pathogenic
(Feb 16, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893377.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Dec 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001209223.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg137*) 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.Arg137*) 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 (rs121907962, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1837283, 18648917, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3904). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Nov 06, 2015)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000331825.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Pathogenic
(Jan 05, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: yes
Allele origin:
germline
|
DASA
Accession: SCV002061148.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the the HEXA gene. It is expected to result in an absent or disrupted protein … (more)
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the the HEXA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3904; PMID: 1532289; 1837283; 9851891; 14685153; 18648917; 22441121; 22789865) - PS4. The variant is present at low allele frequencies population databases (rs121907962– gnomAD 0,00329%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg137*) was detected in trans with a pathogenic variant (PMID: 1837283; 1864891; 9851891; 22441121; 22789865) - PM3_strong. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 1
Sex: male
Geographic origin: Brazil
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Affects
(Apr 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: SCV000024276.64
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 3 that converted arginine-137 to stop. In … (more)
Using chemical mismatch cleavage of PCR-amplified cDNA fragments, Akli et al. (1991) detected a nonsense mutation in exon 3 that converted arginine-137 to stop. In a study of the nature of mutations in non-Jewish patients or carriers of some form of GM2-gangliosidosis (272800), Mules et al. (1992) found a C-to-T transition at nucleotide 409 in exon 3 converting arginine-137 to a stop codon. The family was of possible Irish extraction. (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: SCV002089751.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Variant summary: HEXA c.409C>T (p.Arg137X) 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 2.9e-05 in 277008 control chromosomes. c.409C>T has been reported in the literature in individuals affected with Tay-Sachs Disease (Gort_2012, Mules_1992, Ozkara_1998, Zampieri_2012). These data indicate that the variant is associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg137*) 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 (rs121907962, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1837283, 18648917, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3904). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the the HEXA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3904; PMID: 1532289; 1837283; 9851891; 14685153; 18648917; 22441121; 22789865) - PS4. The variant is present at low allele frequencies population databases (rs121907962– gnomAD 0,00329%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg137*) was detected in trans with a pathogenic variant (PMID: 1837283; 1864891; 9851891; 22441121; 22789865) - PM3_strong. In summary, the currently available evidence indicates that the variant is 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:
The R137X pathogenic variant in the HEXA gene has been reported previously in association with Tay Sachs disease (Akli et al., 1991; Mules et al., 1992). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R137X variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret R137X as a pathogenic variant.
Comment:
Variant summary: HEXA c.409C>T (p.Arg137X) 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 2.9e-05 in 277008 control chromosomes. c.409C>T has been reported in the literature in individuals affected with Tay-Sachs Disease (Gort_2012, Mules_1992, Ozkara_1998, Zampieri_2012). These data indicate that the variant is associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
This sequence change creates a premature translational stop signal (p.Arg137*) 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 (rs121907962, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1837283, 18648917, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3904). For these reasons, this variant has been classified as Pathogenic.
Comment:
The c.409C>T;p.(Arg137*) variant creates a premature translational stop signal in the the HEXA gene. It is expected to result in an absent or disrupted protein product -PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3904; PMID: 1532289; 1837283; 9851891; 14685153; 18648917; 22441121; 22789865) - PS4. The variant is present at low allele frequencies population databases (rs121907962– gnomAD 0,00329%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg137*) was detected in trans with a pathogenic variant (PMID: 1837283; 1864891; 9851891; 22441121; 22789865) - PM3_strong. In summary, the currently available evidence indicates that the variant is 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 |
| Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. | Zampieri S | Gene | 2012 | PMID: 22441121 |
| Newly observed thalamic involvement and mutations of the HEXA gene in a Korean patient with juvenile GM2 gangliosidosis. | Lee SM | Metabolic brain disease | 2008 | PMID: 18648917 |
| Prevalence of lysosomal storage diseases in Portugal. | Pinto R | European journal of human genetics : EJHG | 2004 | PMID: 14685153 |
| At least six different mutations in HEXA gene cause Tay-Sachs disease among the Turkish population. | Ozkara HA | Molecular genetics and metabolism | 1998 | PMID: 9851891 |
| Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
| Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals. | Mules EH | American journal of human genetics | 1992 | PMID: 1532289 |
| 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 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA | - | - | - | - |
Text-mined citations for rs121907962 ...
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.