ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.805+1G>A (rs121907980)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409276 SCV000485219 likely pathogenic Tay-Sachs disease 2016-01-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000409276 SCV000919501 pathogenic Tay-Sachs disease 2017-12-14 criteria provided, single submitter clinical testing Variant summary: The HEXA c.805+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing, which is supported by a functional study (Hechtman_1992). In addition, Gort_2012 observed very little (<10%) HEXA activity in a compound heterozygote affected individual. This variant was found in 1/246234 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). Multiple publications have cited the variant in affected compound heterozygote individuals, predominantly French Canadians. In addition, a clinical diagnostic laboratory and reputable database classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000409276 SCV000933483 pathogenic Tay-Sachs disease 2018-08-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the HEXA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with Tay-Sachs disease (PMID: 22789865), and to segregate with Tay-Sachs disease in several families (PMID: 1483696). This variant is a common cause of disease in the French Canadian population (PMID: 1483696). ClinVar contains an entry for this variant (Variation ID: 3938). This variant is also known as IVS7+1G>A in the literature. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. A different variant affecting this nucleotide (c.805+1G>C) has been determined to be pathogenic (PMID: 7827134). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000004144 SCV000024310 pathogenic Gm2-gangliosidosis, late onset 1992-12-01 no assertion criteria provided literature only

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