Variant summary: The HEXA c.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120572 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant has been reported in many TSD patients both as homozygotes and compound heterozygotes. This variant was shown to be associated with milder phenotype and later onset of disease. Structural studies showed codon R178 to be critical for substrate binding and the reaction intermediates, and R178H is predicted to affect the active site pocket. The effect is lager in R178L and R178C than in R178H, which could explain the difference in clinical phenotype (Ohno_2008). The fact that variants R178L, R178L, and R178H have been reported to be associated with TSD suggest the functional important of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000520.6(HEXA):c.533G>A (p.Arg178His)
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.
(21)
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/Likely pathogenic
21
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.533G>A (p.Arg178His)
Variation ID: 3896 Accession: VCV000003896.64
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 15q23 15: 72353105 (GRCh38) [ NCBI UCSC ] 15: 72645446 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jan 9, 2017 Oct 20, 2024 Jan 13, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000520.6:c.533G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000511.2:p.Arg178His missense NM_000520.5:c.533G>A NM_001318825.2:c.566G>A NP_001305754.1:p.Arg189His missense NR_134869.3:n.575G>A non-coding transcript variant NC_000015.10:g.72353105C>T NC_000015.9:g.72645446C>T NG_009017.2:g.28075G>A P06865:p.Arg178His - Protein change
- R178H, R189H
- Other names
- -
- Canonical SPDI
- NC_000015.10:72353104:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
-
0.00020 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00005
1000 Genomes Project 0.00020
- 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 (1) |
no assertion criteria provided
|
Apr 1, 1992 | RCV000004100.6 | |
|
Hexa, dn allele
|
Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 1992 | RCV000004101.6 |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Nov 16, 2023 | RCV000396083.35 | |
| Pathogenic/Likely pathogenic (13) |
criteria provided, multiple submitters, no conflicts
|
Jan 13, 2024 | RCV000409508.27 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 1, 2019 | RCV001255389.4 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Nov 6, 2017 | RCV002345228.3 | |
|
HEXA-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Jun 19, 2024 | RCV003964792.2 |
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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Pathogenic
(Nov 08, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
paternal
|
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000680256.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Sex: female
Tissue: blood
|
|
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Pathogenic
(Jan 16, 2017)
|
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: SCV000697170.1
First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
Comment:
Variant summary: The HEXA c.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more)
Variant summary: The HEXA c.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120572 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant has been reported in many TSD patients both as homozygotes and compound heterozygotes. This variant was shown to be associated with milder phenotype and later onset of disease. Structural studies showed codon R178 to be critical for substrate binding and the reaction intermediates, and R178H is predicted to affect the active site pocket. The effect is lager in R178L and R178C than in R178H, which could explain the difference in clinical phenotype (Ohno_2008). The fact that variants R178L, R178L, and R178H have been reported to be associated with TSD suggest the functional important of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
|
|
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Pathogenic
(Aug 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: yes
Allele origin:
unknown
|
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Study: Clinvar_gadteam_Clinical_exome_analysis_3
Accession: SCV000803798.1 First in ClinVar: Feb 08, 2018 Last updated: Feb 08, 2018 |
|
|
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Pathogenic
(Dec 04, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000854794.1
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Number of individuals with the variant: 4
Sex: mixed
|
|
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Pathogenic
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001139650.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
|
|
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Pathogenic
(Nov 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Global developmental delay
Affected status: yes
Allele origin:
germline
|
Génétique des Maladies du Développement, Hospices Civils de Lyon
Accession: SCV001431789.1
First in ClinVar: Sep 14, 2020 Last updated: Sep 14, 2020 |
Comment:
homozygous
|
|
|
Pathogenic
(May 22, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002521787.1
First in ClinVar: Jun 03, 2022 Last updated: Jun 03, 2022 |
Comment:
Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000003896, PMID:2961848). Different pathogenic amino acid change has … (more)
Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000003896, PMID:2961848). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000003897, PMID:1833974,2137287). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.993>=0.6, 3CNET: 0.997>=0.75). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Abnormal metabolic brain imaging by MRS (present) , Epileptic encephalopathy (present) , Severe global developmental delay (present)
|
|
|
Pathogenic
(Jan 13, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000893376.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hexosaminidase A deficiency
Affected status: yes
Allele origin:
germline
|
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego
Accession: SCV004046172.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
This variant has been previously reported in patients with Hexosaminidase A deficiency (PMID: 22789865, 1832817). Missense variation is an established mechanism of disease for HEXA-related … (more)
This variant has been previously reported in patients with Hexosaminidase A deficiency (PMID: 22789865, 1832817). Missense variation is an established mechanism of disease for HEXA-related disorders (HGMD). The c.533G>A (p.Arg178His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (12/251014) and thus is presumed to be rare. The c.533G>A (p.Arg178His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.533G>A (p.Arg178His) variant is classified as Pathogenic. (less)
|
|
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Pathogenic
(Dec 09, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV001194029.2
First in ClinVar: Apr 06, 2020 Last updated: Jul 03, 2020 |
Comment:
NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources … (more)
NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources cited for classification include the following: PMID 22441121, 17015493, 2961848, 8730294, 20100466, 22789865, 7551830, 16088929, 1832817 and 2973311. Classification of NM_000520.4(HEXA):c.533G>A(R178H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. (less)
|
|
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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: SCV002061155.1
First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022 |
Comment:
The c.533G>A;p.(Arg178His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3896; PMID: 18490185; 17015493; 16088929; … (more)
The c.533G>A;p.(Arg178His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3896; PMID: 18490185; 17015493; 16088929; 8730294; 7551830; 1318511; 22789865) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1831451) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28941770– gnomAD 0.00001973%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178His) was detected in trans with a pathogenic variant (PMID: 17015493; 16088929; 8730294; 7551830; 22789865) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 3912; 3897) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 8730294) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. (less)
Number of individuals with the variant: 2
Sex: female
Geographic origin: Brazil
|
|
|
Pathogenic
(Aug 01, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: yes
Allele origin:
germline
|
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein
Accession: SCV003807856.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP1 strong, PP3 supporting, PP4
Observation 1:
Number of individuals with the variant: 1
Clinical Features:
Dyskinesia (present) , Cerebellar atrophy (present) , Developmental regression (present) , Absent speech (present) , Cerebral atrophy (present) , Seizure (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Delayed ability to walk (present) , Delayed gross motor development (present) , Generalized hypotonia (present) , Spasticity (present) , Lower limb spasticity (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
Observation 3:
Number of individuals with the variant: 1
Clinical Features:
Dysphagia (present) , Decreased body weight (present) , Developmental regression (present) , Choreoathetosis (present) , Central hypotonia (present) , Seizure (present)
Geographic origin: Brazil
Method: Paired-end whole-genome sequencing
|
|
|
Likely pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
|
Neuberg Centre For Genomic Medicine, NCGM
Accession: SCV004100503.1
First in ClinVar: Nov 04, 2023 Last updated: Nov 04, 2023 |
Comment:
The missense variant p.R178H in HEXA (NM_000520.6) causes the same amino acid change as a previously established pathogenic variant. The R178H variant in the HEXA … (more)
The missense variant p.R178H in HEXA (NM_000520.6) causes the same amino acid change as a previously established pathogenic variant. The R178H variant in the HEXA gene has previously been reported in association with the B1 variant phenotype of TaySachs disease, and is a common pathogenic variant in the Portuguese population (dos Santos et al., 1991). The p.R178H variant is observed in 4/34,556 (0.0116%) alleles from individuals of Latino background in gnomAD Exomes and in 1/1,006 (0.0994%) alleles from individuals of European background in 1000 Genomes. The p.R178H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 178 of HEXA is conserved in all mammalian species. The nucleotide c.533 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Structural analysis of the alpha-subunit of beta-hexosaminidase indicated that the Arginine residue at position 178 is critical for substrate binding. For these reasons, this variant has been classified as Pathogenic. (less)
Clinical Features:
Seizure (present) , Developmental regression (present) , Delayed speech and language development (present) , Atypical behavior (present) , Delayed gross motor development (present) , Dysphagia … (more)
Seizure (present) , Developmental regression (present) , Delayed speech and language development (present) , Atypical behavior (present) , Delayed gross motor development (present) , Dysphagia (present) , Abnormal cerebral white matter morphology (present) , Leukodystrophy (present) (less)
|
|
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Pathogenic
(Jan 13, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Tay-Sachs disease
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000754340.4
First in ClinVar: Feb 08, 2018 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the HEXA protein (p.Arg178His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the HEXA protein (p.Arg178His). This variant is present in population databases (rs28941770, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). It is commonly reported in individuals of Spanish, Portugese, Italian ancestry (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3896). 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 80%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1831451). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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Pathogenic
(Nov 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV002645036.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.R178H pathogenic mutation (also known as c.533G>A), located in coding exon 5 of the HEXA gene, results from a G to A substitution at … (more)
The p.R178H pathogenic mutation (also known as c.533G>A), located in coding exon 5 of the HEXA gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation was first described in trans with a frameshift mutation in a patient diagnosed with Tay-Sachs disease and demonstrating decreased enzymatic activity. In five additional cases from this study, they detected one homozygous and four heterozygous patients, primarily diagnosed in early childhood with a slower progression of disease (Tanaka A, Am. J. Hum. Genet. 1990 Feb; 46(2):329-39). In further studies, individuals homozygous for this mutation present with the juvenile form of Tay-Sachs disease. There is a more variable presentation when this mutation occurs with another pathogenic allele (dos Santos MR, Am. J. Hum. Genet. 1991 Oct; 49(4):886-90 and Gort L, Gene 2012 Sep; 506(1):25-30). This pathogenic mutation results in the B1 variant form of Tay-Sachs disease, which demonstrates normal activity if exposed to artificial substrates but is defective with natural ligand (Gort L, Gene 2012 Sep; 506(1):25-30). Based on the supporting evidence, p.R178H is interpreted as a disease-causing mutation. (less)
|
|
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Pathogenic
(Nov 16, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329360.10
First in ClinVar: Dec 06, 2016 Last updated: Sep 16, 2024 |
Comment:
Common pathogenic variant identified in Spanish, Portuguese, and Italian populations and is associated with late-onset Tay Sachs disease (PMID: 22789865); Not observed at significant frequency … (more)
Common pathogenic variant identified in Spanish, Portuguese, and Italian populations and is associated with late-onset Tay Sachs disease (PMID: 22789865); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22975760, 2521932, 1318511, 21228398, 26286102, 34712575, 10584247, 2973311, 28923328, 16088929, 2961848, 27362553, 1832817, 34440436, 32005694, 31589614, 33240792, 33258288, 18490185, 22789865, 2137287) (less)
|
|
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Pathogenic
(Jul 01, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001249190.26
First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Apr 01, 1992)
|
no assertion criteria provided
Method: literature only
|
TAY-SACHS DISEASE, B1 VARIANT
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024266.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 09, 2018 |
Comment on evidence:
Ohno and Suzuki (1988) defined the mutation in the B1 variant form of Tay-Sachs disease (272800) in a patient of Puerto Rican extraction residing in … (more)
Ohno and Suzuki (1988) defined the mutation in the B1 variant form of Tay-Sachs disease (272800) in a patient of Puerto Rican extraction residing in New York City. The variant was characterized by normal catalytic activity on certain artificial substrates but defective catalytic activity against natural substrates. The so-called DN allele shows a single-base transition at nucleotide 533 from the normal G-to-A within exon 5, resulting in a change from arginine to histidine at amino acid 178. The position of the mutation is about 90 amino acids from the N-terminus of the mature, processed enzyme. Computer analysis predicted substantial alteration in the secondary structure of the enzyme protein. Using two 21-mer oligonucleotide probes with the normal and mutant sequences, Tanaka et al. (1988) found that 4 of 5 other patients of various ethnic origin (Spanish, Italian, Czechoslovakian, French, and English/Italian/Hungarian) showed the same defect. The only case that was completely negative for the DN mutation was the Czechoslovakian patient. These cell lines were tested for the splicing defect at the 5-prime donor site of intron 12 found among Ashkenazi Jewish patients, with negative results in all. Four of the patients, including the original Puerto Rican patient, gave positive signals for both the normal and the mutant probes. Thus these patients were clearly compound heterozygotes. The patient of Spanish origin (residing in Germany) was positive only for the mutant sequence. The parents of this patient came from the same village in Spain, although there was no clear record of consanguinity. The repeated occurrence of this rare mutation in unrelated populations indicates that the biochemical abnormality that defines B1 can be produced in only a limited number of ways. Goebel et al. (1989) described the B1 variant in a 12-year-old girl who suffered from a progressive nerve degenerative disorder marked by ataxia, extrapyramidal symptoms, and convulsions. According to the findings of dos Santos et al. (1991), the B1 variant occurs at an exceptionally high frequency in the northern part of Portugal. In most of the patients there, the disease manifests itself as a juvenile form. In 10 of 11 such patients, dos Santos et al. (1991) found homozygosity for the DN allele; in the other patient, whose clinical profile more closely resembled the late infantile phenotype, compound heterozygosity for the DN allele and another, as yet unidentified abnormal allele was found. Whitley et al. (1992) detected the arg178-to-his mutation by PCR amplification and direct DNA sequencing of exon 5 of the HEXA gene. (less)
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|
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Pathogenic
(Apr 01, 1992)
|
no assertion criteria provided
Method: literature only
|
HEXA, DN ALLELE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000024267.4
First in ClinVar: Apr 04, 2013 Last updated: Apr 09, 2018 |
Comment on evidence:
Ohno and Suzuki (1988) defined the mutation in the B1 variant form of Tay-Sachs disease (272800) in a patient of Puerto Rican extraction residing in … (more)
Ohno and Suzuki (1988) defined the mutation in the B1 variant form of Tay-Sachs disease (272800) in a patient of Puerto Rican extraction residing in New York City. The variant was characterized by normal catalytic activity on certain artificial substrates but defective catalytic activity against natural substrates. The so-called DN allele shows a single-base transition at nucleotide 533 from the normal G-to-A within exon 5, resulting in a change from arginine to histidine at amino acid 178. The position of the mutation is about 90 amino acids from the N-terminus of the mature, processed enzyme. Computer analysis predicted substantial alteration in the secondary structure of the enzyme protein. Using two 21-mer oligonucleotide probes with the normal and mutant sequences, Tanaka et al. (1988) found that 4 of 5 other patients of various ethnic origin (Spanish, Italian, Czechoslovakian, French, and English/Italian/Hungarian) showed the same defect. The only case that was completely negative for the DN mutation was the Czechoslovakian patient. These cell lines were tested for the splicing defect at the 5-prime donor site of intron 12 found among Ashkenazi Jewish patients, with negative results in all. Four of the patients, including the original Puerto Rican patient, gave positive signals for both the normal and the mutant probes. Thus these patients were clearly compound heterozygotes. The patient of Spanish origin (residing in Germany) was positive only for the mutant sequence. The parents of this patient came from the same village in Spain, although there was no clear record of consanguinity. The repeated occurrence of this rare mutation in unrelated populations indicates that the biochemical abnormality that defines B1 can be produced in only a limited number of ways. Goebel et al. (1989) described the B1 variant in a 12-year-old girl who suffered from a progressive nerve degenerative disorder marked by ataxia, extrapyramidal symptoms, and convulsions. According to the findings of dos Santos et al. (1991), the B1 variant occurs at an exceptionally high frequency in the northern part of Portugal. In most of the patients there, the disease manifests itself as a juvenile form. In 10 of 11 such patients, dos Santos et al. (1991) found homozygosity for the DN allele; in the other patient, whose clinical profile more closely resembled the late infantile phenotype, compound heterozygosity for the DN allele and another, as yet unidentified abnormal allele was found. Whitley et al. (1992) detected the arg178-to-his mutation by PCR amplification and direct DNA sequencing of exon 5 of the HEXA gene. (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: SCV002086298.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Pathogenic
(Jun 19, 2024)
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no assertion criteria provided
Method: clinical testing
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HEXA-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004777132.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The HEXA c.533G>A variant is predicted to result in the amino acid substitution p.Arg178His. This variant, also referred as the DN-allele, has been repeatedly reported … (more)
The HEXA c.533G>A variant is predicted to result in the amino acid substitution p.Arg178His. This variant, also referred as the DN-allele, has been repeatedly reported in individuals with Tay-Sachs disease in both the homozygous and compound heterozygous state (Ohno et al. 1988. PubMed ID: 2961848; King et al. 2020. PubMed ID: 33240792; Gort et al. 2012. PubMed ID: 22789865; Montalvo et al. 2005. PubMed ID: 16088929; Maegawa et al. 2006. PubMed ID: 17015493; Giraud et al. 2010. PubMed ID: 20100466). HEXA enzymatic activity in patient's serum and fibroblasts is shown to be significantly reduced (Table 1, Gort et al. 2012. PubMed ID: 22789865). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has been reported as pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3896/). Additionally, different missense changes impacting the same amino acid (p.Arg178Cys and Arg178Leu) have been reported in individuals with Tay-Sachs disease, suggesting that the Arg178 residue is critical to protein function (Tanaka et al. 1990. PubMed ID: 2137287; Triggs-Raine et al. 1991. PubMed ID: 1833974). Taken together, the Arg178His variant is interpreted as pathogenic. (less)
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Comment:
Comment:
homozygous
Comment:
Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000003896, PMID:2961848). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000003897, PMID:1833974,2137287). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.993>=0.6, 3CNET: 0.997>=0.75). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been previously reported in patients with Hexosaminidase A deficiency (PMID: 22789865, 1832817). Missense variation is an established mechanism of disease for HEXA-related disorders (HGMD). The c.533G>A (p.Arg178His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (12/251014) and thus is presumed to be rare. The c.533G>A (p.Arg178His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.533G>A (p.Arg178His) variant is classified as Pathogenic.
Comment:
NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources cited for classification include the following: PMID 22441121, 17015493, 2961848, 8730294, 20100466, 22789865, 7551830, 16088929, 1832817 and 2973311. Classification of NM_000520.4(HEXA):c.533G>A(R178H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The c.533G>A;p.(Arg178His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3896; PMID: 18490185; 17015493; 16088929; 8730294; 7551830; 1318511; 22789865) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1831451) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28941770– gnomAD 0.00001973%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178His) was detected in trans with a pathogenic variant (PMID: 17015493; 16088929; 8730294; 7551830; 22789865) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 3912; 3897) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 8730294) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP1 strong, PP3 supporting, PP4
Comment:
The missense variant p.R178H in HEXA (NM_000520.6) causes the same amino acid change as a previously established pathogenic variant. The R178H variant in the HEXA gene has previously been reported in association with the B1 variant phenotype of TaySachs disease, and is a common pathogenic variant in the Portuguese population (dos Santos et al., 1991). The p.R178H variant is observed in 4/34,556 (0.0116%) alleles from individuals of Latino background in gnomAD Exomes and in 1/1,006 (0.0994%) alleles from individuals of European background in 1000 Genomes. The p.R178H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 178 of HEXA is conserved in all mammalian species. The nucleotide c.533 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Structural analysis of the alpha-subunit of beta-hexosaminidase indicated that the Arginine residue at position 178 is critical for substrate binding. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the HEXA protein (p.Arg178His). This variant is present in population databases (rs28941770, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). It is commonly reported in individuals of Spanish, Portugese, Italian ancestry (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3896). 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 80%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1831451). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R178H pathogenic mutation (also known as c.533G>A), located in coding exon 5 of the HEXA gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation was first described in trans with a frameshift mutation in a patient diagnosed with Tay-Sachs disease and demonstrating decreased enzymatic activity. In five additional cases from this study, they detected one homozygous and four heterozygous patients, primarily diagnosed in early childhood with a slower progression of disease (Tanaka A, Am. J. Hum. Genet. 1990 Feb; 46(2):329-39). In further studies, individuals homozygous for this mutation present with the juvenile form of Tay-Sachs disease. There is a more variable presentation when this mutation occurs with another pathogenic allele (dos Santos MR, Am. J. Hum. Genet. 1991 Oct; 49(4):886-90 and Gort L, Gene 2012 Sep; 506(1):25-30). This pathogenic mutation results in the B1 variant form of Tay-Sachs disease, which demonstrates normal activity if exposed to artificial substrates but is defective with natural ligand (Gort L, Gene 2012 Sep; 506(1):25-30). Based on the supporting evidence, p.R178H is interpreted as a disease-causing mutation.
Comment:
Common pathogenic variant identified in Spanish, Portuguese, and Italian populations and is associated with late-onset Tay Sachs disease (PMID: 22789865); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22975760, 2521932, 1318511, 21228398, 26286102, 34712575, 10584247, 2973311, 28923328, 16088929, 2961848, 27362553, 1832817, 34440436, 32005694, 31589614, 33240792, 33258288, 18490185, 22789865, 2137287)
Comment:
The HEXA c.533G>A variant is predicted to result in the amino acid substitution p.Arg178His. This variant, also referred as the DN-allele, has been repeatedly reported in individuals with Tay-Sachs disease in both the homozygous and compound heterozygous state (Ohno et al. 1988. PubMed ID: 2961848; King et al. 2020. PubMed ID: 33240792; Gort et al. 2012. PubMed ID: 22789865; Montalvo et al. 2005. PubMed ID: 16088929; Maegawa et al. 2006. PubMed ID: 17015493; Giraud et al. 2010. PubMed ID: 20100466). HEXA enzymatic activity in patient's serum and fibroblasts is shown to be significantly reduced (Table 1, Gort et al. 2012. PubMed ID: 22789865). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has been reported as pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3896/). Additionally, different missense changes impacting the same amino acid (p.Arg178Cys and Arg178Leu) have been reported in individuals with Tay-Sachs disease, suggesting that the Arg178 residue is critical to protein function (Tanaka et al. 1990. PubMed ID: 2137287; Triggs-Raine et al. 1991. PubMed ID: 1833974). Taken together, the Arg178His variant is interpreted 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: The HEXA c.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120572 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant has been reported in many TSD patients both as homozygotes and compound heterozygotes. This variant was shown to be associated with milder phenotype and later onset of disease. Structural studies showed codon R178 to be critical for substrate binding and the reaction intermediates, and R178H is predicted to affect the active site pocket. The effect is lager in R178L and R178C than in R178H, which could explain the difference in clinical phenotype (Ohno_2008). The fact that variants R178L, R178L, and R178H have been reported to be associated with TSD suggest the functional important of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Comment:
homozygous
Comment:
Amino acid change identical to known pathogenic variant has been previously reported with established evidence (ClinVar ID: VCV000003896, PMID:2961848). Different pathogenic amino acid change has been reported with sufficient evidence at the same codon (ClinVar ID: VCV000003897, PMID:1833974,2137287). In silico prediction tools and conservation analysis predicted that this variant was probably damaging to the protein structure/function (REVEL: 0.993>=0.6, 3CNET: 0.997>=0.75). It has been reported with an extremely low frequency in the gnomAD v2.1.1 (https://gnomad.broadinstitute.org/) dataset. Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This variant has been previously reported in patients with Hexosaminidase A deficiency (PMID: 22789865, 1832817). Missense variation is an established mechanism of disease for HEXA-related disorders (HGMD). The c.533G>A (p.Arg178His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (12/251014) and thus is presumed to be rare. The c.533G>A (p.Arg178His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.533G>A (p.Arg178His) variant is classified as Pathogenic.
Comment:
NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources cited for classification include the following: PMID 22441121, 17015493, 2961848, 8730294, 20100466, 22789865, 7551830, 16088929, 1832817 and 2973311. Classification of NM_000520.4(HEXA):c.533G>A(R178H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Comment:
The c.533G>A;p.(Arg178His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 3896; PMID: 18490185; 17015493; 16088929; 8730294; 7551830; 1318511; 22789865) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 1831451) - PS3_supporting. The variant is present at low allele frequencies population databases (rs28941770– gnomAD 0.00001973%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg178His) was detected in trans with a pathogenic variant (PMID: 17015493; 16088929; 8730294; 7551830; 22789865) - PM3_strong. Pathogenic missense variant in this residue have been reported (Clinvar ID: 3912; 3897) - PM5. The variant co-segregated with disease in multiple affected family members (PMID: 8730294) - PP1. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic.
Comment:
ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP1 strong, PP3 supporting, PP4
Comment:
The missense variant p.R178H in HEXA (NM_000520.6) causes the same amino acid change as a previously established pathogenic variant. The R178H variant in the HEXA gene has previously been reported in association with the B1 variant phenotype of TaySachs disease, and is a common pathogenic variant in the Portuguese population (dos Santos et al., 1991). The p.R178H variant is observed in 4/34,556 (0.0116%) alleles from individuals of Latino background in gnomAD Exomes and in 1/1,006 (0.0994%) alleles from individuals of European background in 1000 Genomes. The p.R178H missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 178 of HEXA is conserved in all mammalian species. The nucleotide c.533 in HEXA is predicted conserved by GERP++ and PhyloP across 100 vertebrates. Structural analysis of the alpha-subunit of beta-hexosaminidase indicated that the Arginine residue at position 178 is critical for substrate binding. For these reasons, this variant has been classified as Pathogenic.
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 178 of the HEXA protein (p.Arg178His). This variant is present in population databases (rs28941770, gnomAD 0.01%). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). It is commonly reported in individuals of Spanish, Portugese, Italian ancestry (PMID: 1832817, 2961848, 16088929, 17015493, 22441121, 22789865). ClinVar contains an entry for this variant (Variation ID: 3896). 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 80%. Experimental studies have shown that this missense change affects HEXA function (PMID: 1831451). For these reasons, this variant has been classified as Pathogenic.
Comment:
The p.R178H pathogenic mutation (also known as c.533G>A), located in coding exon 5 of the HEXA gene, results from a G to A substitution at nucleotide position 533. The arginine at codon 178 is replaced by histidine, an amino acid with highly similar properties. This pathogenic mutation was first described in trans with a frameshift mutation in a patient diagnosed with Tay-Sachs disease and demonstrating decreased enzymatic activity. In five additional cases from this study, they detected one homozygous and four heterozygous patients, primarily diagnosed in early childhood with a slower progression of disease (Tanaka A, Am. J. Hum. Genet. 1990 Feb; 46(2):329-39). In further studies, individuals homozygous for this mutation present with the juvenile form of Tay-Sachs disease. There is a more variable presentation when this mutation occurs with another pathogenic allele (dos Santos MR, Am. J. Hum. Genet. 1991 Oct; 49(4):886-90 and Gort L, Gene 2012 Sep; 506(1):25-30). This pathogenic mutation results in the B1 variant form of Tay-Sachs disease, which demonstrates normal activity if exposed to artificial substrates but is defective with natural ligand (Gort L, Gene 2012 Sep; 506(1):25-30). Based on the supporting evidence, p.R178H is interpreted as a disease-causing mutation.
Comment:
Common pathogenic variant identified in Spanish, Portuguese, and Italian populations and is associated with late-onset Tay Sachs disease (PMID: 22789865); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22975760, 2521932, 1318511, 21228398, 26286102, 34712575, 10584247, 2973311, 28923328, 16088929, 2961848, 27362553, 1832817, 34440436, 32005694, 31589614, 33240792, 33258288, 18490185, 22789865, 2137287)
Comment:
The HEXA c.533G>A variant is predicted to result in the amino acid substitution p.Arg178His. This variant, also referred as the DN-allele, has been repeatedly reported in individuals with Tay-Sachs disease in both the homozygous and compound heterozygous state (Ohno et al. 1988. PubMed ID: 2961848; King et al. 2020. PubMed ID: 33240792; Gort et al. 2012. PubMed ID: 22789865; Montalvo et al. 2005. PubMed ID: 16088929; Maegawa et al. 2006. PubMed ID: 17015493; Giraud et al. 2010. PubMed ID: 20100466). HEXA enzymatic activity in patient's serum and fibroblasts is shown to be significantly reduced (Table 1, Gort et al. 2012. PubMed ID: 22789865). This variant is reported in 0.012% of alleles in individuals of Latino descent in gnomAD and has been reported as pathogenic by multiple laboratories in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/3896/). Additionally, different missense changes impacting the same amino acid (p.Arg178Cys and Arg178Leu) have been reported in individuals with Tay-Sachs disease, suggesting that the Arg178 residue is critical to protein function (Tanaka et al. 1990. PubMed ID: 2137287; Triggs-Raine et al. 1991. PubMed ID: 1833974). Taken together, the Arg178His variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Intrafamilial Phenotypic Variability and Consequences of Non-Compliance with Treatment in Congenital Adrenal Hyperplasia and Congenital Hypothyroidism within a Single Family . | Improda N | Hormone research in paediatrics | 2017 | PMID: 28359061 |
| 21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia. | Adam MP | - | 2016 | PMID: 20301350 |
| The spectrum of clinical, hormonal and molecular findings in 280 individuals with nonclassical congenital adrenal hyperplasia caused by mutations of the CYP21A2 gene. | Livadas S | Clinical endocrinology | 2015 | PMID: 25041270 |
| In vitro functional studies of rare CYP21A2 mutations and establishment of an activity gradient for nonclassic mutations improve phenotype predictions in congenital adrenal hyperplasia. | Barbaro M | Clinical endocrinology | 2015 | PMID: 24953648 |
| Genotype-phenotype correlation in 1,507 families with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency. | New MI | Proceedings of the National Academy of Sciences of the United States of America | 2013 | PMID: 23359698 |
| 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 |
| Rapid identification of HEXA mutations in Tay-Sachs patients. | Giraud C | Biochemical and biophysical research communications | 2010 | PMID: 20100466 |
| Structural consequences of amino acid substitutions causing Tay-Sachs disease. | Ohno K | Molecular genetics and metabolism | 2008 | PMID: 18490185 |
| The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. | Maegawa GH | Pediatrics | 2006 | PMID: 17015493 |
| 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 |
| Clinical, enzymatic, and molecular characterisation of a Portuguese family with a chronic form of GM2-gangliosidosis B1 variant. | Ribeiro MG | Journal of medical genetics | 1996 | PMID: 8730294 |
| An A-to-G mutation at the +3 position of intron 8 of the HEXA gene is associated with exon 8 skipping and Tay-Sachs disease. | Richard MM | Biochemical and molecular medicine | 1995 | PMID: 7551830 |
| Heterozygosity for the "DN allele" (G533-greater than A) of the beta-hexosaminidase alpha subunit gene identified by direct DNA sequencing in a family with the B1 variant of GM2-gangliosidosis. | Whitley CB | Neuropediatrics | 1992 | PMID: 1318511 |
| 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 |
| GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal. | dos Santos MR | American journal of human genetics | 1991 | PMID: 1832817 |
| Active arginine residues in beta-hexosaminidase. Identification through studies of the B1 variant of Tay-Sachs disease. | Brown CA | The Journal of biological chemistry | 1991 | PMID: 1831451 |
| GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene abnormalities in seven patients. | Tanaka A | American journal of human genetics | 1990 | PMID: 2137287 |
| B1 variant of GM2 gangliosidosis in a 12-year-old patient. | Goebel HH | Pediatric research | 1989 | PMID: 2521932 |
| GM2-gangliosidosis B1 variant: a wide geographic and ethnic distribution of the specific beta-hexosaminidase alpha chain mutation originally identified in a Puerto Rican patient. | Tanaka A | Biochemical and biophysical research communications | 1988 | PMID: 2973311 |
| Mutation in GM2-gangliosidosis B1 variant. | Ohno K | Journal of neurochemistry | 1988 | PMID: 2961848 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HEXA | - | - | - | - |
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Text-mined citations for rs28941770 ...
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Record last updated Nov 19, 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.