Submissions for variant NM_000520.6(HEXA):c.1421+1G>C

gnomAD frequency: 0.00002  dbSNP: rs147324677

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255737	SCV000322422	pathogenic	not provided	2021-04-26	criteria provided, single submitter	clinical testing	Common pathogenic variant in the HEXA gene found in the Ashkenazi Jewish population and associated with infantile onset Tay-Sachs disease (Kaback, M., 2011); Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Functional analysis of c.1421+1 G>C cDNA clones found that this variant results in abnormal gene splicing (Ohno et al. 1988); Kaback, M. and Desnick, R. (Updated [August 11, 2011]) Hexosaminidase A Deficiency In: GeneReviews at Genetests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997- 2015. Available at http://www.genetests.org. Accessed [Nov 2016]; Ohno et al. (1988) Biochem. Biophys. Res. Commun. 153 (1):463-9 (PMID: 2837213);; This variant is associated with the following publications: (PMID: 3362213, 25525159, 22975760, 2837213, 9222766, 2973464, 3375249, 22109873, 29795570, 16088929, 8490625, 1833974, 1387685)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004094	SCV000697163	pathogenic	Tay-Sachs disease	2016-01-19	criteria provided, single submitter	clinical testing	Variant summary: The c.1421+1G>C in HEXA gene alters a conservative nucleotide and mutation Taster predicts a deleterious outcome. 5/5 in silico tools via Alamut predict this variant to have a major effect on splicing pattern. These predictions were confirmed by Ohno et al (1988) who showed that this variants leads to exon12 skipping. This variant has been reported in the literature in multiple affected individuals presented with classic Tay-Sachs disease. This mutation, the second most frequent among Ashkenazi Jews, accounted for approximately 15% of cases in this ethnic group (Montavlo, 2005). The variant is present in the broad control population dataset of ExAC at a low frequency exclusively in European cohort (0.0165%), which does not exceed the maximum frequency for a pathogenic variant in HEXA gene (0.14%). Taking together, the variant was classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000004094	SCV000894056	pathogenic	Tay-Sachs disease	2022-01-16	criteria provided, single submitter	clinical testing
Invitae	RCV000004094	SCV000931129	pathogenic	Tay-Sachs disease	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 12 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is present in population databases (rs147324677, gnomAD 0.2%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 2837213, 2973464, 3362213, 3375249, 9222766). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 16088929). This variant is also known as IVS12+1G>C. ClinVar contains an entry for this variant (Variation ID: 3890). 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.
Myriad Genetics, Inc.	RCV000004094	SCV001194175	pathogenic	Tay-Sachs disease	2019-12-19	criteria provided, single submitter	clinical testing	NM_000520.4(HEXA):c.1421+1G>C is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that c.1421+1G>C is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 3375249, 2837213, 3362213, 9222766 and 2973464. Classification of NM_000520.4(HEXA):c.1421+1G>C 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.
Revvity Omics, Revvity	RCV000004094	SCV002024980	pathogenic	Tay-Sachs disease	2020-06-11	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004094	SCV002768361	pathogenic	Tay-Sachs disease	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RNA studies showed intron 12 retention. However, the authors were unable to predict whether the entire intron or only part of it was retained (PMID: 2837213). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 29 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the three most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar, PMIDs: 2837213, 23852624). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000255737	SCV004564025	pathogenic	not provided	2023-10-23	criteria provided, single submitter	clinical testing	The HEXA c.1421+1G>C variant (rs147324677), also known as IVS12+1G>C, is reported in the medical literature in carriers of Tay-Sachs disease as well as individuals affected with Tay-Sachs disease (Arpaia 1988, Kaufman 1997). This variant is also reported in ClinVar (Variation ID: 3890), and is found in the Ashkenazi Jewish population with an allele frequency of 0.25% (25/10032 alleles) in the Genome Aggregation Database. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function Based on available information, this variant is considered to be pathogenic. References: Arpaia E et al. Identification of an altered splice site in Ashkenazi Tay-Sachs disease. Nature. 1988 May 5;333(6168):85-6. Kaufman M et al. Tay-Sachs disease and HEXA mutations among Moroccan Jews. Hum Mutat. 1997;10(4):295-300.
OMIM	RCV000004094	SCV000024260	affects	Tay-Sachs disease	1997-01-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000004094	SCV002085664	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing