Submissions for variant NM_000520.6(HEXA):c.1274_1277dup (p.Tyr427fs) (rs387906309)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000004093	SCV000218958	pathogenic	Tay-Sachs disease	2018-06-05	criteria provided, single submitter	clinical testing	This sequence change inserts 4 nucleotides in exon 11 of the HEXA mRNA (c.1274_1277dupTATC), causing a frameshift at codon 427. This creates a premature translational stop signal (p.Tyr427Ilefs*5) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXA are known to be pathogenic. This variant is a common pathogenic sequence change in the HEXA gene (PMID: 2848800, 20301397,25287655,24518553, 16352452). It accounts for the majority of Tay-Sachs disease in individuals of Ashkenazi Jewish ancestry with a frequency of up to 80% in obligate carriers (PMID: 2848800, 22975760). This allele is associated with an early-onset phenotype (PMID: 20301397). This variant is also known as c.1277_1278insTATC in the literature. For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	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
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	2019-01-02	criteria provided, single submitter	clinical testing	The c.1274_1277dupTATC variant is one of three common pathogenic variants in the HEXA gene found in the Ashkenazi Jewish population, and is associated with infantile onset Tay-Sachs disease (Kaback, M., 2011). The duplication causes a frameshift starting with codon Tyrosine 427, changes this amino acid to an Isoleucine residue and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Tyr427IlefsX5. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret c.1274_1277dupTATC to be a pathogenic variant.
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,Klinikum rechts der Isar	RCV000004093	SCV000680255	pathogenic	Tay-Sachs disease	2017-11-08	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	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, Partners HealthCare 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	2014-09-07	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Illumina Clinical Services Laboratory,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 Women's Health, 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.
OMIM	RCV000004093	SCV000024259	pathogenic	Tay-Sachs disease	2004-03-01	no assertion criteria provided	literature only
Baylor Genetics	RCV000004093	SCV000328765	pathogenic	Tay-Sachs disease	2015-11-23	no assertion criteria provided	clinical testing	Our laboratory reported dual molecular diagnoses in KMT2D (NM_003482.3, c.2389C>G) and HEXA (NM_000520.4, c.1274_1277dup and c.1073+1G>A in trans) in one individual with reported features which include prematurity, intrauterine growth retardation, severe developmental delay, developmental regression, hypotonia, seizure disorder, microcephaly, short stature, and failure to thrive. Both HEXA variants have been previously reported in patients with Tay-Sachs disease [PMID 1837283, 2848800, 22975760, 21228398, 22344438]. Heterozygotes are expected to be asymptomatic carriers
Counsyl	RCV000004093	SCV000485123	pathogenic	Tay-Sachs disease	2016-02-03	no assertion criteria provided	clinical testing
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