ClinVar Genomic variation as it relates to human health

A heterozygous nonsense variant, NM_212552.2(BOLA3):c.136C>T, has been identified in exon 2 of 4 of the BOLA3 gene. The variant is predicted to result in a premature stop codon at position 46 of the protein (NP_997717.2 (BOLA3):p.(Arg46*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.005% (13 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic (Stutterd, C.A. et al., 2018; Lebigot, E. et al., 2017) and segregated with disease (Baker, P.R. et al., 2014). Additionally, studies show impact in protein function (Lebigot, E. et al., 2017). At least one other pathogenic truncating variant predicted to result in NMD has been reported (ClinVar). Analysis of parental samples indicated this variant was maternally inherited. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

Observed in homozygous state in several unrelated patients with variant non-ketotic hyperglycinemia in published literature (PMID: 24334290, 28803783); 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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29654549, 28803783, 31918395, 32311335, 33574353, 33084218, 35803560, 34440194, 34298071, 35883565, 24334290)

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.005%). This variant was 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 with clinical assertions and evidence for the classification (ClinVar ID: VCV000224514 / PMID: 24334290). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

This sequence change creates a premature translational stop signal (p.Arg46*) in the BOLA3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BOLA3 are known to be pathogenic (PMID: 21944046, 24334290, 26741492). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 224514). This premature translational stop signal has been observed in individual(s) with BOLA3-related conditions (PMID: 24334290). This variant is present in population databases (rs143492730, gnomAD 0.006%).

The observed stop gained c.136C>T(p.Arg46Ter) variant in BOLA3 gene has been reported in homozygous state in individuals affected with BOLA3 related disease (Baker PR 2nd, et. al., 2014). The p.Arg46Ter variant has been reported with allele frequency of 0.004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Pathogenic (multiple submission). The nucleotide change c.136C>T in BOLA3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.