ClinVar Genomic variation as it relates to human health

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.98; 3Cnet: 0.94). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with FLNB -related disorder (ClinVar ID: VCV000038961 / PMID: 16752402). Different missense changes at the same codon (p.Gly168Cys, p.Gly168Val) have been reported to be associated with FLNB -related disorder (ClinVar ID: VCV000812028 / PMID: 22190451). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 168 of the FLNB protein (p.Gly168Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant FLNB-related conditions (PMID: 16752402, 16801345, 22190451). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 38961). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNB protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FLNB function (PMID: 26491051).

The c.502G>A (p.G168S) alteration is located in exon 2 (coding exon 2) of the FLNB gene. This alteration results from a G to A substitution at nucleotide position 502, causing the glycine (G) at amino acid position 168 to be replaced by a serine (S). for autosomal dominant FLNB-related skeletal disorders; however, its clinical significance for autosomal recessive Spondylocarpotarsal synostosis syndrome is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in multiple individuals with features consistent with FLNB-related skeletal disorders, including multiple de novo occurrences (Farrington-Rock, 2006; Bicknell, 2007; Winer, 2009; Petrovski, 2019; Daniel, 2012). Two other alterations at the same codon, c.502G>T (p.G168C) and c.503G>T (p.G168V), have been described individuals with features consistent with FLNB-related skeletal disorders (Daniel, 2012). In an assay testing FLNB function, this variant showed a functionally indeterminant result (Zhao, 2016). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic.