ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.1510C>T (p.Arg504Cys) (rs28942071)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169084 SCV000220258 likely pathogenic Tay-Sachs disease 2014-04-18 criteria provided, single submitter literature only
Integrated Genetics/Laboratory Corporation of America RCV000169084 SCV000917511 pathogenic Tay-Sachs disease 2017-09-18 criteria provided, single submitter clinical testing Variant summary: The HEXA c.1510C>T (p.Arg504Cys) variant causes a missense change involving the alteration of a conserved nucleotide located in the Glycoside hydrolase superfamily domain (IPR017853) (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. One functional study confirmed these predictions by finding no enzymatic activity associated with this variant (Paw_1991). The variant was found in the control population dataset of ExAC in 2/121476 control chromosomes at a frequency of 0.0000165, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant was reported in multiple patients with Tay-Sachs disease, as a homozygous allele (Akli_1991) and in compound heterozygosity with c.805G>A (p.G269S)(pathogenic in our internal database), c.615delG (p.V206X)(not in our internal database, not in HGMD/ClinVar), and c.346+1G>A (not in our internal database, DM in HGMD)(Neudorfer_2005, Montalvo_2005, Akli_1991). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000169084 SCV001139648 pathogenic Tay-Sachs disease 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001000970 SCV001158069 pathogenic not specified 2018-12-17 criteria provided, single submitter clinical testing The HEXA c.1510C>T; p.Arg504Cys variant (rs28942071) has been described in individuals affected with Tay-Sachs disease (TSD; Alki 1991, Montalvo 2005, Neudorfer 2005, Shapiro 2009) and GM2-gangliosidosis (Ragahavan 1985). It contains an entry in ClinVar (Variation ID: 3906) and is observed in the general population at a low overall frequency of 0.0024% (6/251454 alleles) in the Genome Aggregation database. Fibroblasts from patients harboring this variant show reduced beta-hexosaminidase A and defective GM2 ganglioside metabolism (Raghavan 1985). Further analyses of the variant protein demonstrate impaired dimerization and loss of association of alpha and beta subunits (d'Azzo 1984, Paw 1991). Additionally, other variants at this codon (c.1511G>A; p.Arg504His and c.1511G>T; p.Arg504Leu) have been described in individuals affected with TSD (Montalvo 2005, Zampieri 2012). Based on available information, the p.Arg504Cys variant is considered pathogenic. REFERENCES Alki S et al. Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of PCR-amplified cDNA fragments. Genomics. 1991 Sep;11(1):124-34. d'Azzo A et al. Faulty association of alpha- and beta-subunits in some forms of beta-hexosaminidase A deficiency. J Biol Chem. 1984 Sep 10;259(17):11070-4. Montalvo A et al. Molecular analysis of the HEXA gene in Italian patients with infantile and late onset Tay-Sachs disease: detection of fourteen novel alleles. Hum Mutat. 2005 Sep;26(3):282. Neudorfer O et al. Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med. 2005 Feb;7(2):119-23. Paw B et al. A third mutation at the CpG dinucleotide of codon 504 and a silent mutation at codon 506 of the HEX A gene. Am J Hum Genet. 1991 Jun;48(6):1139-46. Raghavan S et al. GM2-ganglioside metabolism in hexosaminidase A deficiency states: determination in situ using labeled GM2 added to fibroblast cultures. Am J Hum Genet. 1985 Nov;37(6):1071-82. Shapiro B et al. Late-onset Tay-Sachs disease presenting as a childhood stutter. J Neurol Neurosurg Psychiatry. 2009 Jan;80(1):94-5. Zampieri S et al. Molecular analysis of HEXA gene in Argentinean patients affected with Tay-Sachs disease: possible common origin of the prevalent c.459+5A>G mutation. Gene. 2012 May 15;499(2):262-5.
OMIM RCV000004112 SCV000024278 pathogenic Gm2-gangliosidosis, chronic 1991-09-01 no assertion criteria provided literature only

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