Submissions for variant NM_000521.4(HEXB):c.841C>T (p.Arg281Ter)

gnomAD frequency: 0.00001  dbSNP: rs138914144

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	RCV000761439	SCV000891521	pathogenic	Sandhoff disease	2017-12-30	criteria provided, single submitter	curation
Labcorp Genetics (formerly Invitae), Labcorp	RCV000761439	SCV001584134	pathogenic	Sandhoff disease	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg281*) in the HEXB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant is present in population databases (rs138914144, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with HEXB-related conditions. ClinVar contains an entry for this variant (Variation ID: 623308). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001562408	SCV001785167	likely pathogenic	not provided	2020-06-26	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31589614, 33287870)
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000761439	SCV004174816	pathogenic	Sandhoff disease	2023-12-08	criteria provided, single submitter	clinical testing	A heterozygous nonsense variation in exon 7 of the HEXB gene that results in a stop codon and premature truncation of the protein at codon 281 was detected. The observed variant c.841C>T (p.Arg281Ter) has not been reported in 1000 genomes and has MAF of 0.002% in gnomAD databases. The in-silico prediction of the variant is disease causing by MutationTaster2 and SpliceAI. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000761439	SCV004805695	pathogenic	Sandhoff disease	2024-03-29	criteria provided, single submitter	clinical testing
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV000761439	SCV005051825	pathogenic	Sandhoff disease	2024-02-01	criteria provided, single submitter	curation
Institute of Human Genetics, University Hospital Muenster	RCV004797868	SCV005419380	likely pathogenic	See cases	2024-09-03	criteria provided, single submitter	clinical testing	ACMG categories: PVS1,PM2
Fulgent Genetics, Fulgent Genetics	RCV000761439	SCV005666637	likely pathogenic	Sandhoff disease	2024-05-04	criteria provided, single submitter	clinical testing