Variant summary: HEXA c.929_930delCT (p.Ser310CysfsX13) 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 (eg. p.Gln390X, p.Tyr427fsX5, p.Arg510X). The variant allele was found at a frequency of 5.3e-05 in 246224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.929_930delCT has been reported in the literature in individuals affected with Tay-Sachs Disease (Fernandes_1992, Nestrasil_2018, Utz_2015, Utz_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.929_930del (p.Ser310fs)
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.929_930del (p.Ser310fs)
Variation ID: 562219 Accession: VCV000562219.83
- Type and length
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Microsatellite, 2 bp
- Location
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Cytogenetic: 15q23 15: 72349135-72349136 (GRCh38) [ NCBI UCSC ] 15: 72641476-72641477 (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 Sep 30, 2018 May 1, 2024 Jan 15, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000520.6:c.929_930del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Ser310fs frameshift NM_000520.6:c.929_930delCT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000520.4:c.929_930delCT NM_001318825.2:c.962_963del NP_001305754.1:p.Ser321fs frameshift NR_134869.3:n.969CT[1] non-coding transcript variant NC_000015.10:g.72349135AG[1] NC_000015.9:g.72641476AG[1] NG_009017.2:g.32042CT[1] - Protein change
- S310fs, S321fs
- Other names
- -
- Canonical SPDI
- NC_000015.10:72349134:AGAG:AG
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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.
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- 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 (7) |
criteria provided, multiple submitters, no conflicts
|
Jan 15, 2024 | RCV000681660.71 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 28, 2019 | RCV001566339.8 |
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
(Jun 27, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
maternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000809107.1
First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018 |
|
|
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Pathogenic
(Jan 22, 2019)
|
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: SCV001362844.1
First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020 |
Comment:
Variant summary: HEXA c.929_930delCT (p.Ser310CysfsX13) 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.929_930delCT (p.Ser310CysfsX13) 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 (eg. p.Gln390X, p.Tyr427fsX5, p.Arg510X). The variant allele was found at a frequency of 5.3e-05 in 246224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.929_930delCT has been reported in the literature in individuals affected with Tay-Sachs Disease (Fernandes_1992, Nestrasil_2018, Utz_2015, Utz_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
|
|
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Pathogenic
(Oct 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001789841.1
First in ClinVar: Aug 19, 2021 Last updated: Aug 19, 2021 |
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 1302612, 25557439) (less)
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Pathogenic
(Jul 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: no
Allele origin:
germline
|
GeneID Lab - Advanced Molecular Diagnostics
Accession: SCV002011812.1
First in ClinVar: Nov 06, 2021 Last updated: Nov 06, 2021 |
Comment:
This variant causes a frameshift; starting at Serine 310, changes this amino acid to a Cysteine residue and creates a premature stop codon in the … (more)
This variant causes a frameshift; starting at Serine 310, changes this amino acid to a Cysteine residue and creates a premature stop codon in the new reading frame, denoted p.Ser310Cysfs*13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This finding is present in the gnomAD exomes database at an allele frequency of 0.0000517. This variant has been described in patiens diagnosed with Tay-Sachs disease (PMID: 1302612, 29352662). Based on these findings we consider this subtitution as "Pathogenic". (less)
Number of individuals with the variant: 1
Age: 30-39 years
Sex: female
Ethnicity/Population group: Caucasian
Geographic origin: United States
|
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Pathogenic
(Nov 05, 2021)
|
criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002813822.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
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Pathogenic
(Jan 15, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001588140.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Ser310Cysfs*13) 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.Ser310Cysfs*13) 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 (rs751248523, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 1302612). ClinVar contains an entry for this variant (Variation ID: 562219). 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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|
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Affects
(Sep 09, 2021)
|
no assertion criteria provided
Method: literature only
|
TAY-SACHS DISEASE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024298.64
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
See 606869.0038.
|
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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: SCV002085689.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
|
Comment:
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 1302612, 25557439)
Comment:
This variant causes a frameshift; starting at Serine 310, changes this amino acid to a Cysteine residue and creates a premature stop codon in the new reading frame, denoted p.Ser310Cysfs*13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This finding is present in the gnomAD exomes database at an allele frequency of 0.0000517. This variant has been described in patiens diagnosed with Tay-Sachs disease (PMID: 1302612, 29352662). Based on these findings we consider this subtitution as "Pathogenic".
Comment:
This sequence change creates a premature translational stop signal (p.Ser310Cysfs*13) 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 (rs751248523, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 1302612). ClinVar contains an entry for this variant (Variation ID: 562219). 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: HEXA c.929_930delCT (p.Ser310CysfsX13) 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 (eg. p.Gln390X, p.Tyr427fsX5, p.Arg510X). The variant allele was found at a frequency of 5.3e-05 in 246224 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (5.3e-05 vs 0.0014), allowing no conclusion about variant significance. c.929_930delCT has been reported in the literature in individuals affected with Tay-Sachs Disease (Fernandes_1992, Nestrasil_2018, Utz_2015, Utz_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 1302612, 25557439)
Comment:
This variant causes a frameshift; starting at Serine 310, changes this amino acid to a Cysteine residue and creates a premature stop codon in the new reading frame, denoted p.Ser310Cysfs*13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This finding is present in the gnomAD exomes database at an allele frequency of 0.0000517. This variant has been described in patiens diagnosed with Tay-Sachs disease (PMID: 1302612, 29352662). Based on these findings we consider this subtitution as "Pathogenic".
Comment:
This sequence change creates a premature translational stop signal (p.Ser310Cysfs*13) 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 (rs751248523, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Tay-Sachs disease (PMID: 1302612). ClinVar contains an entry for this variant (Variation ID: 562219). 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 |
|---|---|---|---|---|
| Distinct progression patterns of brain disease in infantile and juvenile gangliosidoses: Volumetric quantitative MRI study. | Nestrasil I | Molecular genetics and metabolism | 2018 | PMID: 29352662 |
| Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
| A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation. | Fernandes M | Human molecular genetics | 1992 | PMID: 1302612 |
| 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 rs751248523 ...
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.