Submissions for variant NM_001457.4(FLNB):c.1147G>A (p.Gly383Arg)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788356	SCV005400131	likely pathogenic	Spondylocarpotarsal synostosis syndrome	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Like pathogenic. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. Protein-truncating or nonsense mediated decay (NMD) predicted variants are associated with a loss-of-function mechanism, and missense and small in-frame deletion or insertion variants are associated with a gain-of-function mechanism (PMID: 29566257, 22190451, 31836586). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. The recessive condition is caused by biallelic loss-of-function variants and is associated with spondylocarpotarsal synostosis syndrome (MIM#272460). The autosomal dominant FLNB-related disorders (MIM#108720, MIM#108721, MIM#112310, MIM#150250) are mostly caused by gain-of-function variants (PMIDs: 29566257, 22190451). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (3 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. Additionally, as this variant is located close to the intron-exon boundary, splice in silicos also predict an effect on splicing. (SP) 0600 - Variant is located in the annotated filamin/ABP280 repeat domain (DECIPHER). (I) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. This alternative change (p.(Gly383Glu)) has been reported as a VUS (ClinVar). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1206 - This variant has been shown to be paternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Labcorp Genetics (formerly Invitae), Labcorp	RCV005105060	SCV005795480	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 383 of the FLNB protein (p.Gly383Arg). This variant also falls at the last nucleotide of exon 7, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with FLNB-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.