Submissions for variant NM_001457.4(FLNB):c.4061+4G>A

gnomAD frequency: 0.00032  dbSNP: rs370061963

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202688	SCV000257814	uncertain significance	not specified	2015-09-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000727095	SCV000705622	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001146017	SCV001306730	uncertain significance	FLNB-Related Spectrum Disorders	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000727095	SCV001492797	uncertain significance	not provided	2025-01-18	criteria provided, single submitter	clinical testing	This sequence change falls in intron 23 of the FLNB gene. It does not directly change the encoded amino acid sequence of the FLNB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs370061963, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with FLNB-related conditions. ClinVar contains an entry for this variant (Variation ID: 218524). 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 is not likely to affect RNA splicing. 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.
GeneDx	RCV000727095	SCV001757501	likely benign	not provided	2020-03-26	criteria provided, single submitter	clinical testing
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000202688	SCV001984206	uncertain significance	not specified	2020-03-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000727095	SCV002047890	likely benign	not provided	2021-05-12	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277559	SCV002566676	uncertain significance	Connective tissue disorder	2019-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002517345	SCV003548918	likely benign	Inborn genetic diseases	2021-08-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.