Submissions for variant NM_000520.6(HEXA):c.1073+1G>A (rs76173977)

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000079047	SCV000110916	pathogenic	not provided	2012-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004126	SCV000245491	pathogenic	Tay-Sachs disease	2015-07-30	criteria provided, single submitter	clinical testing	This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: in a 25-year-old female [with c.820-7G>A] with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested); in a 1-year-old male [with Y427fs] with IUGR, severe delays with regression, hypotonia, epilepsy, microcephaly, FTT, polymicrogyria, absent HEXA activity. Variant pathogenic in recessive state; heterozygotes are carriers.
Invitae	RCV000004126	SCV000260622	pathogenic	Tay-Sachs disease	2020-10-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 9 of the HEXA gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs76173977, ExAC 0.04%). This is a common variant in Tay-Sachs disease patients of Western European origin (PMID: 8490625, 1387685, 19858779). ClinVar contains an entry for this variant (Variation ID: 3920). Experimental studies have shown that this variant interferes with normal RNA splicing (PMID: 8444467, 1301938). 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.
GeneDx	RCV000079047	SCV000329361	pathogenic	not provided	2018-07-20	criteria provided, single submitter	clinical testing	The c.1073+1 G>A splice site variant in the HEXA gene has been previously reported in association with Tay-Sachs disease (Akli et al., 1991; Akli et al., 1993). This splice site variant destroys the canonical splice donor site in intron 9, and activates a cryptic donor site 17 base pairs downstream, which leads to a shift in the reading frame and a premature Stop codon (Akli et al., 1993). In summary, we interpret c.1073+1 G>A to be a pathogenic variant.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000004126	SCV000584095	pathogenic	Tay-Sachs disease	2014-04-10	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004126	SCV000697161	pathogenic	Tay-Sachs disease	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The HEXA c.1073+1G>A variant involves the alteration of a highly conserved nucleotide in the canonical splice donor site in intron 9. This variant was found in 27/119996 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003776 (25/66208). This frequency is about lower the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant is a known common pathogenic variant mainly found in non-Jewish Caucasian (Landels_1992, Landels_1993, McDowell_1992, Akli_1993, Gort_2012, Utz_2015) with consistent genotype-phenotype and functional data. The frequency in control population therefore represents the carrier frequency. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Fulgent Genetics,Fulgent Genetics	RCV000004126	SCV000894057	pathogenic	Tay-Sachs disease	2018-10-31	criteria provided, single submitter	clinical testing
Myriad Women's Health, Inc.	RCV000004126	SCV001194215	pathogenic	Tay-Sachs disease	2019-11-12	criteria provided, single submitter	clinical testing	NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the c.1073+1G>A variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 8444467, 1387685, 22789865, 17015493, 8490625, 1837283 and 1301938. Classification of NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000079047	SCV001249187	pathogenic	not provided	2018-09-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000079047	SCV001447185	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000004126	SCV001451639	pathogenic	Tay-Sachs disease	2018-08-22	criteria provided, single submitter	clinical testing	The HEXA c.1073+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1073+1G>A variant affects a splice donor site in intron 9 and has been primarily reported in non-Ashkenazi Jewish probands of European descent (Park et al. 2010). Across a selection of available literature, the c.1073+1G>A variant has been identified in a homozygous state in three probands, in a compound heterozygous state in eight probands, in a heterozygous state in five probands in whom a second variant was not identified, and in seven probands in whom zygosity is unknown (Landels et al. 1992; McDowell et al. 1992; Akli et al. 1992; Akerman et al. 1992; Landels et al. 1993; Gort et al. 2012). The c.1073+1G>A variant was also identified in a heterozygous state in 25 unaffected carriers. The c.1073+1G>A variant was absent from 56 control alleles and is reported at a frequency of 0.000388 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis demonstrated that the c.1073+1G>A variant disrupts splicing of the HEXA gene and results in the production of numerous abnormal mRNA products (Akerman et al. 1992). Based on the evidence, the c.1073+1G>A variant is classified as pathogenic for hexoaminidase A deficiency.
OMIM	RCV000004126	SCV000024292	pathogenic	Tay-Sachs disease	1993-06-01	no assertion criteria provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000004126	SCV000494220	pathogenic	Tay-Sachs disease	2014-06-17	no assertion criteria provided	research