ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.533G>A (p.Arg178His) (rs28941770)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000396083 SCV000329360 pathogenic not provided 2018-11-13 criteria provided, single submitter clinical testing The R178H variant in the HEXA gene has previously been reported in association with the B1 variant phenotype of Tay-Sachs disease, and is a common pathogenic variant in the Portuguese population (dos Santos et al., 1991). Structural analysis of the alpha-subunit of beta-hexosaminidase indicated that the Arginine residue at position 178 is critical for substrate binding. The R178H variant results in modest structural changes to the alpha subunit, accounting for the residual enzymatic activity seen and the B1 variant phenotype (Ohno et al., 1988; Ohno et al., 2008). The R178H variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we interpret R178H to be a pathogenic variant.
Institute of Human Genetics,Klinikum rechts der Isar RCV000409508 SCV000680256 pathogenic Tay-Sachs disease 2017-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000409508 SCV000697170 pathogenic Tay-Sachs disease 2017-01-16 criteria provided, single submitter clinical testing Variant summary: The HEXA c.533G>A (p.Arg178His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 8/120572 control chromosomes at a frequency of 0.0000664, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant has been reported in many TSD patients both as homozygotes and compound heterozygotes. This variant was shown to be associated with milder phenotype and later onset of disease. Structural studies showed codon R178 to be critical for substrate binding and the reaction intermediates, and R178H is predicted to affect the active site pocket. The effect is lager in R178L and R178C than in R178H, which could explain the difference in clinical phenotype (Ohno_2008). The fact that variants R178L, R178L, and R178H have been reported to be associated with TSD suggest the functional important of this codon. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000409508 SCV000754340 pathogenic Tay-Sachs disease 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 178 of the HEXA protein (p.Arg178His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs28941770, ExAC 0.02%). This variant is a common cause of Tay-Sachs disease in Spain, Portugal and Italy, although it has also been reported in other populations (PMID: 22789865, 1832817, 16088929, 17015493, 2961848, 22441121). ClinVar contains an entry for this variant (Variation ID: 3896). Experimental studies have shown that this missense change reduces HEXA enzymatic activity towards its nat­u­ral sub­strate, GM2 gan­gli­o­side (PMID: 1831451). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000409508 SCV000803798 pathogenic Tay-Sachs disease 2017-08-07 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000396083 SCV000854794 pathogenic not provided 2017-12-04 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000409508 SCV000893376 pathogenic Tay-Sachs disease 2018-10-31 criteria provided, single submitter clinical testing
Mendelics RCV000409508 SCV001139650 pathogenic Tay-Sachs disease 2019-05-28 criteria provided, single submitter clinical testing
Myriad Women's Health, Inc. RCV000409508 SCV001194029 pathogenic Tay-Sachs disease 2019-12-09 criteria provided, single submitter clinical testing NM_000520.4(HEXA):c.533G>A(R178H) is classified as pathogenic in the context of hexosaminidase A deficiency, and is associated with the juvenile / chronic form of the disease. Sources cited for classification include the following: PMID 22441121, 17015493, 2961848, 8730294, 20100466, 22789865, 7551830, 16088929, 1832817 and 2973311. Classification of NM_000520.4(HEXA):c.533G>A(R178H) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000396083 SCV001249190 pathogenic not provided 2017-07-01 criteria provided, single submitter clinical testing
OMIM RCV000004100 SCV000024266 pathogenic Tay-Sachs disease, B1 variant 1992-04-01 no assertion criteria provided literature only
OMIM RCV000004101 SCV000024267 pathogenic Hexa, dn allele 1992-04-01 no assertion criteria provided literature only
Myriad Women's Health, Inc. RCV000409508 SCV000485125 pathogenic Tay-Sachs disease 2015-12-18 no assertion criteria provided clinical testing

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