ClinVar Genomic variation as it relates to human health

Variant summary: OBSL1 c.4951G>T (p.Glu1651X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. However, the variant is located in an exon which is not expressed / expressed at a low level in several tissues (see e.g. PMID: 17289344 and the GTEx v7 dataset). The variant allele was found at a frequency of 0.0018 in 1606884 control chromosomes in the gnomAD database, including 9 homozygotes (gnomAD v4.0 dataset). The observed variant frequency is approximately 1.6-fold of the estimated maximal expected allele frequency for a pathogenic variant in OBSL1 causing Three M Syndrome 2 phenotype (0.0011), strongly suggesting that the variant is benign. To our knowledge, c.4951G>T has not been reported in the literature in individuals affected with Three M Syndrome 2 and no experimental evidence evaluating its impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 729741). Based on the evidence outlined above, the variant was classified as likely benign.

Reported in a cohort of individuals with cardiovascular disease traits, but additional clinical information was not included (PMID: 31345219); 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: 31345219)

OBSL1: BS2

The OBSL1 p.Glu1651* variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs140825693) and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 532 of 280304 chromosomes (1 homozygous) at a frequency of 0.001898 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 66 of 10342 chromosomes (freq: 0.006382), European (Finnish) in 110 of 25006 chromosomes (freq: 0.004399), Other in 20 of 7132 chromosomes (freq: 0.002804), European (non-Finnish) in 316 of 128214 chromosomes (freq: 0.002465) and Latino in 20 of 35344 chromosomes (freq: 0.000566), but was not observed in the African, East Asian, or South Asian populations. The c.4951G>T variant leads to a premature stop codon at position 1651 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the OBSL1 gene are an established mechanism of disease in Three M Syndrome. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.