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

gnomAD frequency: 0.00009  dbSNP: rs762060470

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics 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	2023-12-14	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. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs762060470, gnomAD 0.02%). This variant has been observed in individuals with Tay-Sachs disease (PMID: 1837283, 22441121, 22789865, 27896118). It is commonly reported in individuals of Spanish and Argentinian ancestry (PMID: 1837283, 22441121, 22789865, 27896118). This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 374505). Variants that disrupt 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. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
GeneDx	RCV000416159	SCV001872715	pathogenic	not provided	2022-07-07	criteria provided, single submitter	clinical testing	Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and functional analysis found this variant results in abnormal splicing (Akli et al., 1991); This variant is associated with the following publications: (PMID: 8044648, 27896118, 22441121, 25525159, 1837283, 9150157, 22723944, 24498621, 22789865, 34426522)
Fulgent Genetics, Fulgent Genetics	RCV000416449	SCV002808684	pathogenic	Tay-Sachs disease	2022-03-08	criteria provided, single submitter	clinical testing
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
Natera, Inc.	RCV000416449	SCV002089748	pathogenic	Tay-Sachs disease	2017-03-16	no assertion criteria provided	clinical testing