NM_000520.4(HEXA):c.[574G>C;598G>A] AND Tay-Sachs disease, B1 variant

Clinical significance:Pathogenic (Last evaluated: Jul 1, 1996)

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000004129.2

Alleles description [Variation Report for NM_000520.4(HEXA):c.[574G>C;598G>A]]

NM_000520.5(HEXA):c.574G>C (p.Val192Leu)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.5(HEXA):c.574G>C (p.Val192Leu)
HGVS:
  • NC_000015.10:g.72351231C>G
  • NG_009017.1:g.29949G>C
  • NM_000520.5:c.574G>C
  • NP_000511.2:p.Val192Leu
  • NC_000015.9:g.72643572C>G
  • NM_000520.4:c.574G>C
  • NR_134869.1:n.1075G>C
  • P06865:p.Val192Leu
Protein change:
V192L; VAL192LEU
Links:
UniProtKB: P06865#VAR_003212; OMIM: 606869.0036; dbSNP: rs387906310
NCBI 1000 Genomes Browser:
rs387906310
Molecular consequence:
  • NM_000520.5:c.574G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134869.1:n.1075G>C - non-coding transcript variant - [Sequence Ontology: SO:0001619]

NM_000520.5(HEXA):c.598G>A (p.Val200Met)

Gene:
HEXA:hexosaminidase subunit alpha [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
15q23
Genomic location:
Preferred name:
NM_000520.5(HEXA):c.598G>A (p.Val200Met)
HGVS:
  • NC_000015.10:g.72351207C>T
  • NG_009017.1:g.29973G>A
  • NM_000520.5:c.598G>A
  • NP_000511.2:p.Val200Met
  • NC_000015.9:g.72643548C>T
  • NM_000520.4:c.598G>A
  • NR_134869.1:n.1099G>A
  • P06865:p.Val200Met
Protein change:
V200M; VAL200MET
Links:
UniProtKB: P06865#VAR_003215; OMIM: 606869.0036; dbSNP: rs1800429
NCBI 1000 Genomes Browser:
rs1800429
Molecular consequence:
  • NM_000520.5:c.598G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NR_134869.1:n.1099G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:
Tay-Sachs disease, B1 variant
Identifiers:
MedGen: C1848916

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000024295OMIMno assertion criteria providedPathogenic
(Jul 1, 1996)
germlineliterature only

PubMed (4)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only

Citations

PubMed

Tay-Sachs disease: B1 variant.

Gordon BA, Gordon KE, Hinton GG, Cadera W, Feleki V, Bayleran J, Hechtman P.

Pediatr Neurol. 1988 Jan-Feb;4(1):54-7.

PubMed [citation]
PMID:
2976595

A double mutation in exon 6 of the beta-hexosaminidase alpha subunit in a patient with the B1 variant of Tay-Sachs disease.

Ainsworth PJ, Coulter-Mackie MB.

Am J Hum Genet. 1992 Oct;51(4):802-9.

PubMed [citation]
PMID:
1415222
PMCID:
PMC1682773
See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000024295.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (4)

Description

In a patient with the B1 variant form of Tay-Sachs disease (272800) described by Gordon et al. (1988), Ainsworth and Coulter-Mackie (1992) found a double mutation in exon 6 of HEXA: a G-to-C transversion of nucleotide 574 causing a val192-to-leu substitution, and a G-to-A transition at nucleotide 598 resulting in a val200-to-met substitution. Transient expression studies of the 2 exon-6 mutations (singly or together) in COS-1 cells showed that the val192-to-leu change was sufficient to cause the loss of enzyme activity. Furthermore, the biochemical phenotype of this alteration in transfection studies was consistent with that expected for a B1 variant mutation. Coulter-Mackie (1994) reported that the paternally derived allele carried the IVS9DS mutation described in 606869.0033. Subsequently, Hou et al. (1996) demonstrated that the val192-to-leu mutation in the alpha subunit of HEXA is not associated with the B1 variant form of Tay-Sachs disease. Most mutations in the alpha-subunit of HEXA that result in Tay-Sachs disease affect the initial folding of the pro-alpha chain in the endoplasmic reticulum, resulting in its retention and degradation. A much less common occurrence is a mutation that specifically affects an 'active site' residue necessary for substrate binding and/or catalysis. In this case, hexosaminidase A is present in the lysosome, but it lacks all alpha-specific activity. This is the biochemical phenotype of the B1 variant form of TSD. Hou et al. (1996) examined permanently cotransfected Chinese hamster ovary cells with an alpha-cDNA-construct including the val192-to-leu substitution and a mutant beta-cDNA, beta-arg211 to lys, encoding a beta subunit that is inactive but normal in all other respects. They found that the val192-to-leu substitution produced a pro-alpha chain that did not form alpha-beta dimers and was not transported to the lysosome. Furthermore, they reexamined the hexosaminidase activity and protein levels in the fibroblasts from the original patient. These data were also not consistent with the biochemical phenotype of the B1 variant of Tay-Sachs disease. Thus, they concluded that the val192-to-leu substitution does not specifically affect the alpha-active site.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 17, 2019

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