Submissions for variant NM_000521.4(HEXB):c.1597C>T (p.Arg533Cys)

gnomAD frequency: 0.00003  dbSNP: rs764552042

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000502357	SCV000595122	pathogenic	Sandhoff disease	2016-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502357	SCV000919509	pathogenic	Sandhoff disease	2018-10-26	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.1597C>T (p.Arg533Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 246212 control chromosomes (gnomAD and publication). c.1597C>T has been reported in the literature in multiple compound heterozygous and homozygous individuals affected with Sandhoff Disease with limited or absent Hex activity (Gort_2012, Aryan_2012, Kaya_2011, Zampieri_2012). These data indicate that the variant is very likely to be associated with disease. Two CllinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000502357	SCV001228728	pathogenic	Sandhoff disease	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 533 of the HEXB protein (p.Arg533Cys). This variant is present in population databases (rs764552042, gnomAD 0.006%). This missense change has been observed in individual(s) with Sandhoff disease (PMID: 21567908, 22848519, 23010210, 27682710). ClinVar contains an entry for this variant (Variation ID: 435415). 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 HEXB protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HEXB function (PMID: 22848519). For these reasons, this variant has been classified as Pathogenic.
Centogene AG - the Rare Disease Company	RCV000502357	SCV001424439	pathogenic	Sandhoff disease		criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000502357	SCV002024990	pathogenic	Sandhoff disease	2021-03-16	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000502357	SCV002801454	pathogenic	Sandhoff disease	2022-01-04	criteria provided, single submitter	clinical testing
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV000502357	SCV002820229	pathogenic	Sandhoff disease		criteria provided, single submitter	clinical testing	The missense variant p.R533C in HEXB (NM_000521.3) has been previously reported in affected patients including thosefrom Indian origin (Tamhankar et al, 2016).It has been reported in the ClinVar database as a Pathogenic variant.The p.R533C variant is observed in 2/30,604(0.0065%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in1000 Genomes.There is a large physicochemical difference between arginine and cysteine, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties.The p.R533C missense variant is predicted to be damaging by both SIFT and PolyPhen2.The arginine residue at codon 533 of HEXB is conserved in all mammalian species.The nucleotide c.1597 in HEXB is predicted conserved by GERP++ and PhyloP across 100 vertebrates.For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000502357	SCV000797401	likely pathogenic	Sandhoff disease	2018-01-30	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000502357	SCV001457618	pathogenic	Sandhoff disease	2020-09-16	no assertion criteria provided	clinical testing
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000502357	SCV001469235	pathogenic	Sandhoff disease	2020-09-10	no assertion criteria provided	clinical testing