Submissions for variant NM_001110556.2(FLNA):c.1406C>T (p.Pro469Leu)

gnomAD frequency: 0.00002  dbSNP: rs782434140

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000640745	SCV000762344	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 469 of the FLNA protein (p.Pro469Leu). This variant is present in population databases (rs782434140, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. ClinVar contains an entry for this variant (Variation ID: 533575). 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 expected to disrupt FLNA protein function with a positive predictive value of 80%. 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	RCV000723066	SCV001823028	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 533575; Landrum et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Ambry Genetics	RCV003303028	SCV003997931	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-04-10	criteria provided, single submitter	clinical testing	The p.P469L variant (also known as c.1406C>T), located in coding exon 8 of the FLNA gene, results from a C to T substitution at nucleotide position 1406. The proline at codon 469 is replaced by leucine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of <0.01% (5/198448) total alleles studied, with 2 hemizygote(s) observed. The highest observed frequency was <0.01% (5/89867) of European (non-Finnish) alleles. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Gharavi Laboratory, Columbia University	RCV000723066	SCV000854197	uncertain significance	not provided	2018-09-16	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV004735694	SCV005357185	uncertain significance	FLNA-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The FLNA c.1406C>T variant is predicted to result in the amino acid substitution p.Pro469Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0056% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.