ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs782161982
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae 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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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