Submissions for variant NM_001110556.2(FLNA):c.5255T>C (p.Leu1752Pro)

gnomAD frequency: 0.00001  dbSNP: rs1363194253

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762687	SCV000893022	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	FLNA: PM2, PP2
Labcorp Genetics (formerly Invitae), Labcorp	RCV001201534	SCV001372609	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1744 of the FLNA protein (p.Leu1744Pro). This variant is not present in population databases (gnomAD no frequency). 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: 624458). 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 FLNA protein function with a negative predictive value of 95%. 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	RCV000762687	SCV001998551	uncertain significance	not provided	2022-09-14	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Institute of Human Genetics, University Hospital Muenster	RCV004584410	SCV002577990	uncertain significance	See cases	2022-05-31	criteria provided, single submitter	clinical testing	ACMG categories: PM2
PreventionGenetics, part of Exact Sciences	RCV004535894	SCV004727675	uncertain significance	FLNA-related disorder	2023-12-17	no assertion criteria provided	clinical testing	The FLNA c.5255T>C variant is predicted to result in the amino acid substitution p.Leu1752Pro. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.