Submissions for variant NM_000520.6(HEXA):c.806-7G>A

gnomAD frequency: 0.00006  dbSNP: rs770932296

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV000191092	SCV000245490	pathogenic	Tay-Sachs disease	2014-07-02	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found once in our laboratory in trans with another pathogenic variant [c.1073+1G>A] in a 25-year-old female with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested). Variant pathogenic in recessive state; heterozygotes are carriers.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000191092	SCV000917520	likely pathogenic	Tay-Sachs disease	2023-03-07	criteria provided, single submitter	clinical testing	Variant summary: HEXA c.806-7G>A alters a non-conserved nucleotide located close 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: Two predict the variant abolishes the canonical intron 7 - 3' splice acceptor site. Two predict the variant weakens the canonical intron 7 - 3' splice acceptor site. Three predict the variant creates a new intronic 3' splice acceptor site located 5 nucleotides upstream of the normal canonical intron 7 - 3' splice acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Fernandes_1997). The study demonstrated that this variant leads to a reduction in steady state levels of HEXA mRNA and production of an abnormally spliced mRNA species with exon 8 deleted. The variant allele was found at a frequency of 2.4e-05 in 250368 control chromosomes. c.806-7G>A has been reported in the literature as a compound heterozygous genotype in at-least one individual affected with Tay-Sachs Disease (example, Fernandes_1997). The same publication also reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 5% of normal Hexosaminidase A enzyme activity measured in the fibroblasts of the individual with the compound heterozygous genotype. As a control measurement, the Hexosaminidase A enzyme activity in the fibroblasts of a carrier of the other allele was 57%, consistent with the carrier genotype. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus as Likely Pathogenic (n=2)/Pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000191092	SCV000932244	pathogenic	Tay-Sachs disease	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. This variant is present in population databases (rs770932296, gnomAD 0.005%). This variant has been observed in individual(s) with clinical features of Tay-Sachs disease (PMID: 9272736; Invitae; externalcommunication). 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: 209160). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001582679	SCV001471674	likely pathogenic	not provided	2019-08-30	criteria provided, single submitter	clinical testing	The HEXA c.806-7G>A variant (rs770932296) is reported in the literature in an individual affected with chronic GM2-gangliosidosis that also carried a second pathogenic variant (Fernandes 1997). This variant is found on only seven chromosomes (7/281768 alleles) in the Genome Aggregation Database. This is an intronic variant in a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic acceptor splice site. Indeed, analyses of mRNAs from an individual carrying this variant indicates a >80% decrease in mRNA levels and skipping of exon 8 (Fernandes 1997). Based on available information, this variant is considered to be likely pathogenic. References: Fernandes MJ et al. A chronic GM2 gangliosidosis variant with a HEXA splicing defect: quantitation of HEXA mRNAs in normal and mutant fibroblasts. Eur J Hum Genet. 1997 May-Jun;5(3):129-36.
GeneDx	RCV001582679	SCV001812599	pathogenic	not provided	2019-11-29	criteria provided, single submitter	clinical testing	Introduces a new splice acceptor site upstream of the normal intron 7 splice acceptor site and leads to a more than 80% reduction of steady-state HEXA mRNA levels (Fernandes et al., 1997); In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17001642, 9272736, 26633545)
Revvity Omics, Revvity	RCV000191092	SCV002023465	likely pathogenic	Tay-Sachs disease	2021-04-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000191092	SCV002060354	uncertain significance	Tay-Sachs disease	2021-11-09	criteria provided, single submitter	clinical testing	NM_000520.4(HEXA):c.806-7G>A is an intronic variant classified as a variant of uncertain significance in the context of hexosaminidase A deficiency. c.806-7G>A has been observed in cases with relevant disease (PMID: 9272736). Functional assessments of this variant are available in the literature (PMID: 9272736). c.806-7G>A has been observed in population frequency databases (gnomAD: NFE 0.01%). In summary, there is insufficient evidence to classify NM_000520.4(HEXA):c.806-7G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Center for Human Genetics Tuebingen	RCV001582679	SCV005051347	likely pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	HEXA: PM3:Strong, PM2, PS3:Supporting
OMIM	RCV000004146	SCV000024312	pathogenic	Gm2-gangliosidosis, chronic	1992-12-01	no assertion criteria provided	literature only