ClinVar Genomic variation as it relates to human health

The c.263dupG variant in the B4GALNT1 gene has been reported previously in the homozygous state in an individual with hereditary spastic paraplegia with learning disability, lower limb spasticity and weakness, nystagmus, axonal sensitive neuropathy, white matter hyperintensities, and cerebral atrophy (Boukhris et al., 2013). The c.263dupG variant causes a frameshift starting with codon Leucine 89, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Leu89ProfsX13. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.263dupG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.263dupG as a likely pathogenic variant.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 60525). This premature translational stop signal has been observed in individual(s) with hereditary spastic paraplegia (PMID: 23746551, 32214227). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Leu89Profs*13) in the B4GALNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in B4GALNT1 are known to be pathogenic (PMID: 23746551).

The p.Leu89ProfsX13 variant in B4GALNT1 has been reported in the homozygous state, in at least 3 individuals with hereditary spastic paraplegia (Boukhris 2013 PMID: 23746551, Rose 2020 PMID: 31812852, Hengel 2020 PMID: 32214227). At least two of these individuals were from consanguineous parents. This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 60525) and has been identified in 0.01% (5/67846) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This is consistent with the prevalence of the disease in the general population. In vitro functional studies provide some evidence that this variant impacts protein function as in vitro cell-free enzyme assays showed no residual enzyme activity for this variant (Bhuiyan 2019 PMID: 30521973). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 89 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the B4GALNT1 gene is an established disease mechanism in autosomal recessive hereditary spastic paraplegia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hereditary spastic paraplegia. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting, PS3_Supporting.

PM2, PM3, PS3, PVS1