Submissions for variant NM_000521.4(HEXB):c.1417G>A (p.Gly473Ser)

gnomAD frequency: 0.00001  dbSNP: rs762892362

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414444	SCV000491081	likely pathogenic	not provided	2016-10-03	criteria provided, single submitter	clinical testing	The G473S variant in the HEXB gene has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The G473S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G473S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000414444	SCV001762104	likely pathogenic	not provided	2021-06-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984275	SCV001774727	likely pathogenic	Sandhoff disease	2022-09-28	criteria provided, single submitter	clinical testing	Variant summary: HEXB c.1417G>A (p.Gly473Ser) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251440 control chromosomes (gnomAD). c.1417G>A has been reported in the literature in individuals affected with Sandhoff Disease or related disease (Sung_2018, Rowe_2021, Salamon_2021). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000414444	SCV002497330	likely pathogenic	not provided	2022-04-01	criteria provided, single submitter	clinical testing	HEXB: PM2, PM3, PP3, PP4
Invitae	RCV000984275	SCV003271478	pathogenic	Sandhoff disease	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 473 of the HEXB protein (p.Gly473Ser). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is present in population databases (rs762892362, gnomAD 0.0009%). This missense change has been observed in individual(s) with late-onset Sandhoff disease (PMID: 30065954, 34856081). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372685). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Counsyl	RCV000984275	SCV001132417	uncertain significance	Sandhoff disease	2019-04-23	no assertion criteria provided	clinical testing