Submissions for variant NM_001457.4(FLNB):c.572C>T (p.Pro191Leu)

gnomAD frequency: 0.00005  dbSNP: rs368472521

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413979	SCV000491295	likely pathogenic	not provided	2016-01-12	criteria provided, single submitter	clinical testing	The P191L variant in the FLNB gene has been reported previously as a de novo change in a patient with Larsen syndrome (Daniel et al., 2012). The P191L variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P191L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position in the CH2 domain that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S188P, W189R, W189G) have been reported in the Human Gene Mutation Database in association with FLNB-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. The P191L variant is a strong candidate for a pathogenic variant,which may be related to the short stature, facial dysmorphism, and skeletal findings reported in this individual and the short stature reported in this individual's mother. However, the possibility it may be a rare benign variant cannot be excluded.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001196906	SCV001367540	uncertain significance	Atelosteogenesis type III	2020-01-30	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PP3.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000413979	SCV004278811	uncertain significance	not provided	2023-07-18	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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) performed at Invitae indicates that this missense variant is not expected to disrupt FLNB protein function. ClinVar contains an entry for this variant (Variation ID: 372794). This missense change has been observed in individual(s) with Larsen syndrome (PMID: 22190451). This variant is present in population databases (rs368472521, gnomAD 0.01%). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 191 of the FLNB protein (p.Pro191Leu).