Submissions for variant NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs)

gnomAD frequency: 0.00046  dbSNP: rs387906309

Total submissions: 36

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000004093	SCV000218958	pathogenic	Tay-Sachs disease	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr427Ilefs*5) in the HEXA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs387906309, gnomAD 1.3%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individuals with Tay-Sachs disease (PMID: 2848800, 16352452, 20301397, 24518553, 25287655). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 2848800, 22975760). This variant is also known as c.1277_1278insTATC. ClinVar contains an entry for this variant (Variation ID: 3889). 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.
Eurofins Ntd Llc (ga)	RCV000224443	SCV000225230	pathogenic	not provided	2015-04-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000004093	SCV000247559	pathogenic	Tay-Sachs disease	2014-08-15	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224443	SCV000281445	pathogenic	not provided	2015-06-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000004093	SCV000328765	pathogenic	Tay-Sachs disease	2022-05-27	criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000004093	SCV000538041	pathogenic	Tay-Sachs disease	2015-09-26	criteria provided, single submitter	clinical testing	The c.1274_1277dupTATC, (p.Tyr427Ilefs*5) is a known frameshift variant that has been shown to result in the absence of mRNA. To that effect, the majority of pathogenic variants in the Ashkenazi Jewish TSD are null alleles, making it a common mechanism of disease. Moreover, this 4 basepair insertion variant has been reported in the majority of affected individuals of Ashkenazi Jewish ancestry (Myerowitz and Costigan, 1988), and has not been seen in the normal population databases (1000 Genomes, ExAc, and Exome Sequencing Project [ESP]). In summary, this variant is best classified as a recessive pathogenic variant for Tay-Sachs disease.
GeneDx	RCV000224443	SCV000565056	pathogenic	not provided	2024-08-20	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 (PMID: 20301397); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8352284, 2848800, 30609409, 22975760, 25287655, 14727180, 8488832, 1830584, 2294750, 27033294, 1307230, 28503624, 21228398, 27959697, 29352662, 28333917, 30548430, 31076878, 31980526, 33083013, 33240792, 1387685, 37267771, 35586607, 35848209, 34554397, 33831955, 20301397)
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000004093	SCV000584094	pathogenic	Tay-Sachs disease	2014-07-10	criteria provided, single submitter	research
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000004093	SCV000680255	pathogenic	Tay-Sachs disease	2017-11-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000004093	SCV000697162	pathogenic	Tay-Sachs disease	2017-08-21	criteria provided, single submitter	clinical testing	Variant summary: This c.1274_1277dupTATC (p.Tyr427Ilefs) results in a premature termination codon, predicted to cause a truncated or absent HEXA protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One functional study found less than 5% b-Hexosaminidase activity in leukocytes from a patient with Tay-Sachs disease carrying this variant in compound heterozygosity with p.R510H (not in our internal database)(Udwadia-Hedge_2017). This variant was found in the large control database ExAC in 92/121426 control chromosomes at a frequency of 0.0007577, which does not exceed the maximal expected frequency of a pathogenic allele (0.0013975) in this gene. This variant has been reported as a common pathogenic variant found especially in Ashkenazi Jews population with consistent clinical and genetic data (Myerowitz_1988, Jamali_2014, Zampieri_2012). Multiple clinical labs as well as reputable databases have classified this variant as pathogenic. Taken together, this variant has been classified as pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000004093	SCV000712205	pathogenic	Tay-Sachs disease	2017-05-18	criteria provided, single submitter	clinical testing	The p.Tyr427IlefsX5 (NM_000520.4 c.1274_1277dupTATC) variant in HEXA is a common pathogenic variant that has been reported in many compound heterozygous and hom ozygous individuals with Tay-Sachs disease (Myerowitz 1988, Montalvo 2005, Scott 2010, Gort 2012, Zampieri 2012, Jamail 2014). It has been reported in ClinVar ( Variation ID#3889) as pathogenic by multiple laboratories. This variant has been identified in 1.3% (135/10152) of Ashkenazi Jewish chromosomes and 0.03% (48/12 6682) of European chromosomes by the Genome Aggregation Database (gnomAD, http:/ /gnomad.broadinstitute.org; dbSNP rs387906309). Although this variant has been s een in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 427 and le ads to a premature termination codon 5 amino acids downstream. This alteration i s then predicted to lead to a truncated or absent protein. Biallelic loss of fun ction in the HEXA gene is an established disease mechanism for Tay-Sachs disease . In summary, this variant meets criteria to be classified as pathogenic for Ta y-Sachs disease in an autosomal recessive manner based upon a predicted null eff ect and its biallelic occurrence in individuals with this disease.
Ambry Genetics	RCV000623223	SCV000743019	pathogenic	Inborn genetic diseases	2021-12-27	criteria provided, single submitter	clinical testing	The c.1274_1277dupTATC (p.Y427Ifs*5) alteration, located in coding exon 11 of the HEXA gene, consists of a duplication of TATC at position 1274, causing a translational frameshift with a predicted alternate stop codon after 5 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of 0.07% (210/282850) total alleles studied. The highest observed frequency was 1.29% (134/10370) of Ashkenazi Jewish alleles. This mutation is the most common Tay-Sachs disease alteration found in the Ashkenazi Jewish population (Myerowitz, 1988) and has been shown to account for approximately 80% of all mutant HEXA Ashkenazi Jewish alleles (Kaback, 1993; Scott, 2010). Based on the available evidence, this alteration is classified as pathogenic.
Illumina Laboratory Services, Illumina	RCV000004093	SCV000914692	pathogenic	Tay-Sachs disease	2018-08-29	criteria provided, single submitter	clinical testing	The HEXA c.1274_1277dupTATC (p.Tyr427IlefsTer5) variant results in a frameshift and is predicted to result in premature termination of the protein. Across a selection of the available literature, the p.Tyr427IlefsTer5 variant has been identified in eight probands in a homozygous state, two probands in a compound heterozygous state and in five probands with unknown zygosity (Myerowitz et al. 1988; McDowell et al. 1992; Jamali et al. 2014; Sheth et al. 2014). The c.1274_1277dupTATC (p.Tyr427IlefsTer5) the most common HEXA variant in the Ashkenazi Jewish population and accounts for approximately 80% of variant HEXA alleles in this population (Kaback et al. 2011). Segregation of the variant with the disease has been shown in at least two families (Myerowitz et al. 1988). The variant was found in 69 of 2238 controls in a heterozygous state and is reported at a frequency of 0.00157 in the European American population of the Exome Sequencing Project. Due to the potential impact of frameshift variants, the p.Tyr427IlefsTer5 variant is classified as pathogenic for hexosaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Myriad Genetics, Inc.	RCV000004093	SCV001193865	pathogenic	Tay-Sachs disease	2019-10-18	criteria provided, single submitter	clinical testing	NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the Y427Ifs*5 variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 2848800, 1307230, 1830584, 11463833, and 14727180. Classification of NM_000520.4(HEXA):c.1274_1277dupTATC(Y427Ifs*5) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.
Centogene AG - the Rare Disease Company	RCV001250227	SCV001424435	pathogenic	Tay-Sachs disease, variant AB; Tay-Sachs disease		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224443	SCV001747734	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	HEXA: PVS1, PM2, PM3
Revvity Omics, Revvity	RCV000004093	SCV002024978	pathogenic	Tay-Sachs disease	2021-11-18	criteria provided, single submitter	clinical testing
New York Genome Center	RCV000004093	SCV002506704	pathogenic	Tay-Sachs disease	2021-06-07	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital Muenster	RCV000004093	SCV002526129	pathogenic	Tay-Sachs disease	2022-05-30	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PS4,PP5,BS1
Daryl Scott Lab, Baylor College of Medicine	RCV000004093	SCV002567942	pathogenic	Tay-Sachs disease	2022-08-22	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000004093	SCV002579636	pathogenic	Tay-Sachs disease	2021-12-03	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000004093	SCV002768489	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) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0305 - Variant is present in gnomAD (v2) >=0.01 and <0.03 for a recessive condition (210 heterozygotes, 0 homozygotes). (I) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It is one of the most common variants to cause Tay-Sachs disease in the Ashkenazi Jewish population (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	RCV000004093	SCV004032467	pathogenic	Tay-Sachs disease	2023-03-29	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000004093	SCV004242410	pathogenic	Tay-Sachs disease	2024-01-02	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM3_VSTR,PM2_SUP
Neuberg Centre For Genomic Medicine, NCGM	RCV000004093	SCV005042632	pathogenic	Tay-Sachs disease	2023-05-20	criteria provided, single submitter	clinical testing	The frameshift c.1274_1277dup (p.Tyr427IlefsTer5) variant in the HEXA gene has been observed in individuals with Tay-Sachs disease (Vallance, Hilary et al.,2006). This variant is also known as c.1277_1278insTATC. It is commonly reported in individuals of Ashkenazi Jewish ancestry (Lazarin, Gabriel A et al.,2013). The p.Tyr427IlefsTer5 variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Tyrosine 427, changes this amino acid to Isoleucine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Tyr427IlefsTer5. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. Enzyme analysis is recommended.
Mayo Clinic Laboratories, Mayo Clinic	RCV000224443	SCV005414291	pathogenic	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000224443	SCV005625801	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	The HEXA c.1274_1277dup (p.Tyr427Ilefs*5) variant alters the translational reading frame of the HEXA mRNA and causes the premature termination of HEXA protein synthesis. This variant has been described in the published literature as a common pathogenic variant in the Ashkenazi Jewish population (PMIDs: 14727180 (2004), 8230592 (1993), 2848800 (1988)). It has been reported in homozygous individuals with severe infantile Tay-Sachs disease (TSD) (PMIDs: 34554397 (2021), 33083013 (2020)27896118 (2014)), as well as in compound heterozygous individuals with additional pathogenic HEXA variants in juvenile TSD (PMID: 33240792 (2020)) and late onset TSD (PMID: 35848209 (2022), 31076878 (2019), 27033294 (2016)). Functional studies have shown nonsense mediated decay as the disease mechanism for the variant (PMID: 114638363 (2001)), resulting in little to no enzyme activity (PMIDs: 27896118 (2014), 2848800 (1988)). Based on the available information, this variant is classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224443	SCV005875597	pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	The HEXA c.1274_1277dup; p.Tyr427IlefsTer5 variant (rs387906309) is reported in the literature in the homozygous or compound heterozygous state in individuals affected with early-onset Tay-Sachs disease and is one of the most common pathogenic HEXA variants found in the Ashkenazi Jewish population (Bell 2011, Lazarin 2013, Myerowitz 1988, Paw 1990, Posey 2017, Toro 2020, Vissers 2017, Zeesman 2015). This variant is reported in ClinVar (Variation ID: 3889) and is found in the Ashkenazi Jewish population with an allele frequency of 1.3% (134/10,370 alleles) in the Genome Aggregation Database (v2.1.1). This variant causes a frameshift by inserting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay and is associated with the absence of protein in patient cells (Myerowitz 1988). Based on available information, the p.Tyr427IlefsTer5 variant is considered to be pathogenic. References: Bell CJ et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med. 2011 Jan 12;3(65):65ra4. PMID: 21228398. Lazarin GA et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. 2013 Mar;15(3):178-86. PMID: 22975760. Myerowitz R and Costigan FC. The major defect in Ashkenazi Jews with Tay-Sachs disease is an insertion in the gene for the alpha-chain of beta-hexosaminidase. J Biol Chem. 1988 Dec 15;263(35):18587-9. PMID: 2848800. Paw BH et al. Frequency of three Hex A mutant alleles among Jewish and non-Jewish carriers identified in a Tay-Sachs screening program. Am J Hum Genet. 1990 Oct;47(4):698-705. PMID: 2220809. Posey JE et al. Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. N Engl J Med. 2017 Jan 5;376(1):21-31. PMID: 27959697. Toro C et al. HEXA Disorders. GeneReviews. 2020. (https://www.ncbi.nlm.nih.gov/books/NBK1218/). PMID: 20301397. Vissers LELM et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017 Sep;19(9):1055-1063. PMID: 28333917. Zeesman S et al. Prader-Willi syndrome and Tay-Sachs disease in association with mixed maternal uniparental isodisomy and heterodisomy 15 in a girl who also had isochromosome Xq. Am J Med Genet A. 2015 Jan;167A(1):180-4. PMID: 25287655.
OMIM	RCV000004093	SCV000024259	affects	Tay-Sachs disease	2004-03-01	no assertion criteria provided	literature only
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000004093	SCV000494223	pathogenic	Tay-Sachs disease	2014-09-11	no assertion criteria provided	research
Reproductive Health Research and Development, BGI Genomics	RCV000004093	SCV001142451	pathogenic	Tay-Sachs disease	2020-01-06	no assertion criteria provided	curation	NM_000520.4:c.1274_1277dupTATC in the HEXA gene has an allele frequency of 0.013 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant is located at the 11th exon (14 exons in the NM_000520.4 transcript), therefore, it is predicted to lead nonsense-mediated mRNA decay. The c.1274_1277dupTATC (p.Tyr427Ilefs*5) variant has been reported multiple times and is determiend as the most common disease-causing variant in the Ashkenazi Jewis (PMID: 20672374). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PVS1; PS4; PP4
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252517	SCV001428274	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224443	SCV001798857	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224443	SCV001973862	pathogenic	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000004093	SCV002085670	pathogenic	Tay-Sachs disease	2017-03-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004755708	SCV005346811	pathogenic	HEXA-related disorder	2024-07-16	no assertion criteria provided	clinical testing	The HEXA c.1274_1277dupTATC variant is predicted to result in a frameshift and premature protein termination (p.Tyr427Ilefs*5). This is among the most common pathogenic variants in HEXA and is responsible for up to 80% of documented cases of Tay-Sachs Disease in the Ashkenzi Jewish population (Myerowitz et al. 1988. PubMed ID: 2848800; Kaback et al. 1993. PubMed ID: 20301397). This variant is interpreted as pathogenic.