Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
  • Chr15:72346234 (on Assembly GRCh38)
  • Chr15:72638575 (on Assembly GRCh37)
Other names:
  • IVS12, G-C, +1
  • NG_009017.1:g.34946G>C
  • NM_000520.4:c.1421+1G>C
  • NC_000015.10:g.72346234C>G (GRCh38)
  • NC_000015.9:g.72638575C>G (GRCh37)
NCBI 1000 Genomes Browser:
Molecular consequence:
NM_000520.4:c.1421+1G>C: splice donor variant [Sequence Ontology SO:0001575]
Allele frequency:
GO-ESP 0.00023 (G)

Clinical significance


Clinical significance:
Review status:
2 stars out of maximum of 4 stars
classified by multiple submitters
Number of submission(s):
See supporting ClinVar records

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Recent activity

Assertion and evidence details


Clinical significance
(Last evaluated)
Review status
(Assertion method)
Collection methodCondition(s)
(Mode of inheritance)
OriginCitationsSubmitter - Study name
(Last submitted)
Submission accession
(Apr 20, 2015)
classified by single submitter
(literature only)
literature onlygermlinePubMed (5)
[See all records that cite these PMIDs]

(Dec 30, 2010)



FamiliesIndividualsSegregationAllele originEthnicityGeographic origin
not providednot providednot providedgermlinenot providednot provided


Data published from literature

FamiliesIndividualsSegregationsAllele originCitations
not providednot providednot providedgermline


Arpaia et al. (1988) identified a single-base mutation in a cloned fragment of the HEXA gene from an Ashkenazi Jewish patient with Tay-Sachs disease (272800). The change, a G-to-C substitution in the first nucleotide of intron 12, was expected to result in defective splicing of the mRNA. A test for the mutant allele based on amplification of DNA by the PCR and cleavage of a DdeI restriction site generated by the mutation showed that this case and 2 other cases of the Ashkenazi, infantile form of Tay-Sachs disease are heterozygous for 2 different mutations. The mutation was found in over 20% of the Tay-Sachs alleles that they examined in Ashkenazi Jewish patients and carriers but in none of 43 normal Jewish persons. Arpaia et al. (1988) suggested that the occurrence of multiple mutant alleles in Ashkenazim warrants further examination of the selective advantage hypothesis; the hypothesis of founder effect suggests the existence of a single mutant allele. In a case of classic infantile Tay-Sachs disease in an Ashkenazi Jewish patient, Ohno and Suzuki (1988) found that there were 2 types of Hex-A mRNA: intact mRNA and mRNA with truncated intron 12 sequences. Sequence analysis showed a single G-to-C nucleotide transversion at the 5-prime donor site of intron 12, the same change as that in the patient of Arpaia et al. (1988). Both patients were compound heterozygotes. Myerowitz (1988) likewise found in each of 2 unrelated Ashkenazi patients that 1 alpha-chain allele harbored the splice junction mutation. Only 1 parent of each of these patients was positive for the defect. Thirty percent of obligate heterozygotes tested carried the splice junction mutation, whereas 20 Ashkenazi Jews designated noncarriers by enzymatic assay were negative for this alteration. In an Ashkenazi Jewish child with Tay-Sachs disease and a splicing defect at the 5-prime donor site of intron 12, present in heterozygous state, Ohno and Suzuki (1988) found a variety of abnormal mRNAs.
This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 13% of cases in this ethnic group. Strasberg et al. (1997) reported the first incidence of homozygosity for the intron 12 mutation in a female infant with classic TSD. The child first presented at the age of 13.5 months with seizures associated with fever and pneumococcal bacteremia. Developmental delay had been recognized from early in life with no history of regression or exaggerated startle reflex. At 13 months, she showed central hypotonia and peripheral hypertonia with exaggerated deep tendon reflexes and bilateral ankle clonus. Funduscopy revealed bilateral cherry red spots of the macula.

Last Updated: Apr 23, 2015