ClinVar Miner

Submissions for variant NM_000520.5(HEXA):c.1274_1277dup (p.Tyr427Ilefs) (rs387906309)

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Total submissions: 16
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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.
OMIM RCV000004093 SCV000024259 pathogenic Tay-Sachs disease 2004-03-01 no assertion criteria provided literature only
Baylor Miraca Genetics Laboratories, 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,Institute of Human Genetics RCV000004093 SCV000494223 pathogenic Tay-Sachs disease 2014-09-11 no assertion criteria provided research

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