ClinVar Genomic variation as it relates to human health

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.

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.

PS3, PS4_moderate, PM2, PM3, PM5, PP1, PP4

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 504 of the HEXA protein (p.Arg504Cys). This variant is present in population databases (rs28942071, gnomAD 0.006%). This missense change has been observed in individual(s) with Tay–Sachs disease (PMID: 1837283, 19091716, 25860343). ClinVar contains an entry for this variant (Variation ID: 3906). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXA function (PMID: 9694901). For these reasons, this variant has been classified as Pathogenic.

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) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (6 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2 and 3) (highest allele count: 3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with Tay-Sachs disease (PMIDs: 16088929, 15714079). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1,PP3.