ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.1444G>A (p.Glu482Lys)
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.1444G>A (p.Glu482Lys)
Variation ID: 3892 Accession: VCV000003892.84
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 15q23 15: 72345528 (GRCh38) [ NCBI UCSC ] 15: 72637869 (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 Oct 11, 2015 May 1, 2024 Dec 25, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000520.6:c.1444G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Glu482Lys missense NM_001318825.2:c.1477G>A NP_001305754.1:p.Glu493Lys missense NR_134869.3:n.1229G>A non-coding transcript variant NC_000015.10:g.72345528C>T NC_000015.9:g.72637869C>T NG_009017.2:g.35652G>A P06865:p.Glu482Lys - Protein change
- E482K, E493K
- Other names
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- Canonical SPDI
- NC_000015.10:72345527:C:T
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00003
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 |
1127 | 1161 |
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
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
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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 (5) |
criteria provided, multiple submitters, no conflicts
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Dec 25, 2023 | RCV000004096.80 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Aug 27, 2021 | RCV002512734.7 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 8, 2022 | RCV003480020.1 |
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
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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
(May 05, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003934606.1
First in ClinVar: Jun 24, 2023 Last updated: Jun 24, 2023 |
Comment:
Variant summary: HEXA c.1444G>A (p.Glu482Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded … (more)
Variant summary: HEXA c.1444G>A (p.Glu482Lys) results in a conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251424 control chromosomes. c.1444G>A has been reported in the literature as a homozygous genotype in multiple individuals affected with Tay-Sachs Disease and in settings of multigene panel testing for neurological disorders (example, Nakano_1988, Akli_1993 overlapping Poenaru_1994, Montalvo_2005, Ganapathy_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dersh_2019). The most pronounced variant effect results in abolishment of enzymatic activity against MUGS substrate, unprocessed by lysosomal proteases and altered folding as compared to the wild-type enzyme. This study also demonstrated that this variant retrotranslocated from the endoplasmic reticulum (ER) to the cytosol and was degraded by the proteasome, indicating clearance via ER-associated degradation (ERAD). The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 27682588, 31069529, 16088929, 2970528, 7858168). Four 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Likely pathogenic
(Aug 27, 2021)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003571847.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1444G>A (p.E482K) alteration is located in exon 13 (coding exon 13) of the HEXA gene. This alteration results from a G to A substitution … (more)
The c.1444G>A (p.E482K) alteration is located in exon 13 (coding exon 13) of the HEXA gene. This alteration results from a G to A substitution at nucleotide position 1444, causing the glutamic acid (E) at amino acid position 482 to be replaced by a lysine (K). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (2/251424) total alleles studied. This alteration has been reported in patients with Tay-Sachs disease (Nakano, 1988; Montalvo, 2005). Based on internal structural analysis, this variant is highly destabilizing to the local structure (Novak, 1994; Hou, 1996; Hou, 1998; Hepbildikler, 2002; Lemieux, 2006). Enzymatic activity was undetectable in both cultured patient fibroblasts and cells transiently expressing p.E482K. In addition, p.E482K was severely misfolded and degraded by the proteosome (Brown, 1993; Dersh, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
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Pathogenic
(May 06, 2021)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002767346.1
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) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated glycosyl hydrolase family 20, catalytic domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. It has been reported in at least two patients with Tay Sachs disease and has been classified as likely pathogenic by a diagnostic laboratory (ClinVar; PMID: 1301190, 2970528, 16088929). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1001 - This variant has strong functional evidence supporting abnormal protein function. Studies on patient fibroblasts demonstrated markedly reduced enzymatic activities and in vitro analysis demonstrated this is due to altered folding and inability to be secreted (PMID: 27682588). (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign (less)
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Likely pathogenic
(Feb 10, 2016)
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criteria provided, single submitter
Method: clinical testing
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Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000485717.2
First in ClinVar: Oct 11, 2015 Last updated: Dec 24, 2022 |
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Pathogenic
(Dec 08, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV004226678.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
PP3, PM2, PM3, PS3, PS4_moderate
Number of individuals with the variant: 1
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Pathogenic
(Dec 25, 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: SCV002170069.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 482 of the HEXA protein … (more)
This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 482 of the HEXA protein (p.Glu482Lys). This variant is present in population databases (rs121907952, gnomAD 0.006%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 1301190, 2970528, 9338583, 16088929). ClinVar contains an entry for this variant (Variation ID: 3892). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1301190, 8328462, 27682588). For these reasons, this variant has been classified as Pathogenic. (less)
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Affects
(Aug 01, 2008)
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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: SCV000024262.66
First in ClinVar: Apr 04, 2013 Last updated: May 01, 2024 |
Comment on evidence:
In a non-Jewish case of Tay-Sachs disease (272800), Proia and Neufeld (1982) found a normal amount of alpha chain of beta-hexosaminidase synthesized in a cell-free … (more)
In a non-Jewish case of Tay-Sachs disease (272800), Proia and Neufeld (1982) found a normal amount of alpha chain of beta-hexosaminidase synthesized in a cell-free translation system using RNA from cultured fibroblasts of the patient. (RNA from fibroblasts of 4 other patients, 3 Jewish and 1 non-Jewish, did not direct the translation of immunoprecipitable alpha chain. In the same system, RNA from fibroblasts of 2 patients with Sandhoff disease did not direct translation of immunoprecipitable beta chain.) Intact fibroblasts from the atypical patient likewise synthesized the alpha chain as shown by labeling with (3H)leucine; however, strong detergent was required for extraction. The alpha chain could be labeled with (3H)mannose but not with (32P)phosphate; it was neither secreted nor accumulated in the proteolytically processed form, and it disappeared within a day of synthesis. The authors suggested that a plausible but not unique explanation is that the insoluble alpha chain is not transported from the endoplasmic reticulum (the site of glycosylation) to the Golgi apparatus (the site of phosphorylation) nor to the further destinations--lysosomes and the exterior of the cell. Nakano et al. (1988) isolated cDNA clones from cultured fibroblasts of this patient, who was Italian. Sequence analysis showed a single nucleotide substitution, from G to A, at nucleotide 1444, which resulted in a change from glutamic acid to lysine at amino acid 482. The change from the strongly negative to strongly positive charge at amino acid 482 was thought to be responsible for the defective processing of the enzyme in this patient. Akalin et al. (1992) demonstrated the same mutation in a case of classic TSD in a Chinese patient. Using structural modeling, Ohno et al. (2008) found that the glu482 residue is buried within the folded enzyme and the E482K mutation affects atoms throughout the whole enzyme, which correlated with a more severe phenotype. (less)
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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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In-silico screening and microsecond molecular dynamics simulations to identify single point mutations that destabilize β-hexosaminidase A causing Tay-Sachs disease. | Almanasra A | Proteins | 2021 | PMID: 34288098 |
In silico analysis of the effects of disease-associated mutations of β-hexosaminidase A in Tay-Sachs disease. | Ihsan Fazal M | Journal of genetics | 2020 | PMID: 32529985 |
Genotype-phenotype correlation of gangliosidosis mutations using in silico tools and homology modeling. | Ou L | Molecular genetics and metabolism reports | 2019 | PMID: 31367523 |
Multi-gene testing in neurological disorders showed an improved diagnostic yield: data from over 1000 Indian patients. | Ganapathy A | Journal of neurology | 2019 | PMID: 31069529 |
Tay-Sachs disease mutations in HEXA target the α chain of hexosaminidase A to endoplasmic reticulum-associated degradation. | Dersh D | Molecular biology of the cell | 2016 | PMID: 27682588 |
Structural consequences of amino acid substitutions causing Tay-Sachs disease. | Ohno K | Molecular genetics and metabolism | 2008 | PMID: 18490185 |
Evaluation of the risk for Tay-Sachs disease in individuals of French Canadian ancestry living in new England. | Martin DC | Clinical chemistry | 2007 | PMID: 17259242 |
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 |
Physiological substrates for human lysosomal beta -hexosaminidase S. | Hepbildikler ST | The Journal of biological chemistry | 2002 | PMID: 11707436 |
A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic Sandhoff disease. | Hou Y | The Journal of biological chemistry | 1998 | PMID: 9694901 |
W474C amino acid substitution affects early processing of the alpha-subunit of beta-hexosaminidase A and is associated with subacute G(M2) gangliosidosis. | Petroulakis E | Human mutation | 1998 | PMID: 9603435 |
Tay-Sachs disease and HEXA mutations among Moroccan Jews. | Kaufman M | Human mutation | 1997 | PMID: 9338583 |
Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. | Myerowitz R | Human mutation | 1997 | PMID: 9090523 |
Bacterial chitobiase structure provides insight into catalytic mechanism and the basis of Tay-Sachs disease. | Tews I | Nature structural biology | 1996 | PMID: 8673609 |
Direct determination of the substrate specificity of the alpha-active site in heterodimeric beta-hexosaminidase A. | Hou Y | Biochemistry | 1996 | PMID: 8672428 |
Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as substrate. | Novak A | Biochimica et biophysica acta | 1994 | PMID: 8123671 |
Molecular epidemiology of Tay-Sachs disease in Europe. | Poenaru L | Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie | 1994 | PMID: 7858168 |
Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients. | Akli S | Human molecular genetics | 1993 | PMID: 8490625 |
beta-Hexosaminidase isozymes from cells cotransfected with alpha and beta cDNA constructs: analysis of the alpha-subunit missense mutation associated with the adult form of Tay-Sachs disease. | Brown CA | American journal of human genetics | 1993 | PMID: 8328462 |
Novel Tay-Sachs disease mutations from China. | Akalin N | Human mutation | 1992 | PMID: 1301190 |
A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant. | Nakano T | Journal of neurochemistry | 1988 | PMID: 2970528 |
Synthesis of beta-hexosaminidase in cell-free translation and in intact fibroblasts: an insoluble precursor alpha chain in a rare form of Tay-Sachs disease. | Proia RL | Proceedings of the National Academy of Sciences of the United States of America | 1982 | PMID: 6959123 |
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Text-mined citations for rs121907952 ...
HelpRecord last updated May 01, 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.