ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.459+5G>A (rs762060470)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416159 SCV000493277 likely pathogenic not provided 2017-02-01 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000416449 SCV000584097 pathogenic Tay-Sachs disease 2017-02-09 criteria provided, single submitter research
Invitae RCV000416449 SCV000754339 pathogenic Tay-Sachs disease 2019-11-05 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs762060470, ExAC 0.02%). This variant is a common cause of Tay-Sachs disease in Spain and Argentina, although it has also been found in other populations (PMID: 1837283, 22789865, 22441121, 27896118). This variant is also known as IVS4+5G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 374505). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000416449 SCV000917513 pathogenic Tay-Sachs disease 2017-09-08 criteria provided, single submitter clinical testing Variant summary: The HEXA c.459+5G>A (aka IVS4+5G>A) is a splice-site variant that alters a highly conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, with functional studies confirming that this variant leads to exon 4 skipping and NMD. The variant is present in control datasets of ExAC and gnomAD at a low frequency of 0.000028 (3/120932 and 8/ 277156 chrs tested, respectively). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0013. The variant has been reported in affected individuals with confirmed Tay-Sachs disease via publications and is cited as Pathogenic/Likely Pathogenic by a reputable database/clinical laboratories. Taken together, this variant is classified as pathogenic.
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000416449 SCV000494206 pathogenic Tay-Sachs disease 2012-09-22 no assertion criteria provided research

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