ClinVar Genomic variation as it relates to human health

Variant summary: The HEXB c.850C>T (p.Arg284X) variant results in a premature termination codon, predicted to cause a truncated or absent HEXB protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 8/277214 control chromosomes at a frequency of 0.0000289, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXB variant (0.001479). The variant has been identified in numerous patients as both a homozygous and compound heterozygous allele. Functional studies suggest that HEXB enzyme activity is severely affected, though these studies are complicated by the fact that the variant causes HEXB to be heat-sensitive, which is the major method of separating HEXA and HEXB activity. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

A compound heterozygous status for the variant c.850C>T (p.Arg284Ter) in Exon 7 of the HEXB gene was detected. The variants have not been reported in the 1000 genomes database and has a MAF of 0.003% in the gnomAD database. The in-silico prediction is disease causing by Mutation Taster and DANN. In summary, the variant meets our criteria to be classified as pathogenic.

Observed in multiple unrelated individuals with Sandhoff disease (PMID: 8162015, 24613245, 23046579); Reported both with a second pathogenic variant on the opposite allele (in trans) and in the apparently homozygous state in affected individuals, and not observed in homozygous state in controls (PMID: 8162015, 24613245, 23046579); 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; This variant is associated with the following publications: (PMID: 26020229, 21483992, 24613245, 23046579, 1532910, 25525159, 19282776, 23430803, 18758829, 29448188, 30075786, 33083013, 34554397, 8162015)

Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000003887, PMID:8162015). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency:0.0000278). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

The stop gained p.R284* in HEXB (NM_000521.4) has been reported previously in multipel affected patients with Sandhoff disease including patients of Indian origin (Mahdieh N et al,Tamhankar PM et al). It has been submitted to ClinVar as Pathogenic. The p.R284* variant is observed in 7/30,616 (0.0229%) alleles from individuals of South Asian background in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant is predicted to cause loss of normal protein function through protein truncation. For these reasons, this variant has been classified as Pathogenic.

A Homozygote Nonsense variant c.850C>T in Exon 7 of the HEXB gene that results in the amino acid substitution p.Arg284* was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic(Vaiant ID 3887).This variant has been previously reported in Zhang Z-X et al., 1994. Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.

This sequence change creates a premature translational stop signal (p.Arg284*) 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 (rs121907986, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Sandhoff disease (PMID: 8162015, 18758829, 23046579, 24613245, 26582265, 29448188). ClinVar contains an entry for this variant (Variation ID: 3887). For these reasons, this variant has been classified as Pathogenic.