Submissions for variant NM_001110556.2(FLNA):c.4183C>T (p.Pro1395Ser)

gnomAD frequency: 0.00004  dbSNP: rs782161982

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001309469	SCV001498967	uncertain significance	Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1395 of the FLNA protein (p.Pro1395Ser). This variant is present in population databases (rs782161982, gnomAD 0.005%). 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: 1011642). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FLNA protein function. 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	RCV002253803	SCV002525232	uncertain significance	not provided	2022-06-01	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 has a deleterious effect on protein structure/function
Ambry Genetics	RCV002327688	SCV002628497	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-03-10	criteria provided, single submitter	clinical testing	The p.P1395S variant (also known as c.4183C>T), located in coding exon 24 of the FLNA gene, results from a C to T substitution at nucleotide position 4183. The proline at codon 1395 is replaced by serine, an amino acid with similar properties. Based on data from gnomAD, the T allele has an overall frequency of 0.0022% (4/181214) total alleles studied, with 3 hemizygotes observed. The highest observed frequency was 0.0049% (4/81184) of European (non-Finnish) alleles. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004782702	SCV005395624	uncertain significance	not specified	2024-09-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734113	SCV005351251	uncertain significance	FLNA-related disorder	2024-05-15	no assertion criteria provided	clinical testing	The FLNA c.4183C>T variant is predicted to result in the amino acid substitution p.Pro1395Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0049% 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.