ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.4243A>C (p.Ile1415Leu)

gnomAD frequency: 0.00001  dbSNP: rs2067686132
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001318117 SCV001508806 uncertain significance Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 2023-01-28 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 1018767). This variant has not been reported in the literature in individuals affected with FLNA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1415 of the FLNA protein (p.Ile1415Leu).
GeneDx RCV001760390 SCV001988981 uncertain significance not provided 2019-05-09 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
New York Genome Center RCV001836985 SCV002097885 uncertain significance Heterotopia, periventricular, X-linked dominant 2020-06-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV002329276 SCV002628651 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2021-12-20 criteria provided, single submitter clinical testing The p.I1415L variant (also known as c.4243A>C), located in coding exon 24 of the FLNA gene, results from an A to C substitution at nucleotide position 4243. The isoleucine at codon 1415 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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