ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.1242G>A (p.Lys414=)

gnomAD frequency: 0.00001  dbSNP: rs1309123671
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000674299 SCV000799611 likely pathogenic Sandhoff disease 2018-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000674299 SCV002511535 likely pathogenic Sandhoff disease 2022-04-19 criteria provided, single submitter clinical testing Variant summary: HEXB c.1242G>A (p.Lys414Lys) located at the last nucleotide of the exon alters a conserved nucleotide located adjacent to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant abolishes the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in exon 10 skipping (example, Gomez-Lira_1998). The variant allele was found at a frequency of 4e-06 in 251298 control chromosomes. c.1242G>A has been reported in the literature as a homozygous and compound heterozygous genotype in at-least two individuals affected with Sandhoff Disease (example, Gomez-Lira_1998, Sobek_2012). These data indicate that the variant may be associated with disease. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000674299 SCV004293744 pathogenic Sandhoff disease 2023-11-05 criteria provided, single submitter clinical testing This sequence change affects codon 414 of the HEXB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXB protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has been observed in individual(s) with Sandhoff disease (PMID: 9475608, 23010210). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558077). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 10 and introduces a premature termination codon (PMID: 9475608). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.

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