Submissions for variant NM_001457.4(FLNB):c.502G>A (p.Gly168Ser)

dbSNP: rs80356504

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001596945	SCV001832259	pathogenic	not provided	2019-10-11	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV003152668	SCV003841697	likely pathogenic	Larsen syndrome	2023-02-23	criteria provided, single submitter	clinical testing	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.
Center for Personalized Medicine, Children's Hospital Los Angeles	RCV003156065	SCV003845233	likely pathogenic	See cases	2022-12-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001596945	SCV004293106	pathogenic	not provided	2023-09-04	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FLNB function (PMID: 26491051). 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. ClinVar contains an entry for this variant (Variation ID: 38961). 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. This variant is not present in population databases (gnomAD no frequency). 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).
Ambry Genetics	RCV004619190	SCV005117810	pathogenic	Inborn genetic diseases	2024-05-31	criteria provided, single submitter	clinical testing	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.
GeneReviews	RCV004528149	SCV000055805	not provided	FLNB-related disorder		no assertion provided	literature only