ClinVar Miner

Submissions for variant NM_001110556.2(FLNA):c.6776T>C (p.Phe2259Ser)

gnomAD frequency: 0.00001  dbSNP: rs1276647740
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV002233679 SCV000828569 uncertain significance Heterotopia, periventricular, X-linked dominant; Melnick-Needles syndrome; Oto-palato-digital syndrome, type II; Frontometaphyseal dysplasia 2023-07-29 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2251 of the FLNA protein (p.Phe2251Ser). This variant is present in population databases (no rsID available, gnomAD 0.001%). 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: 577159). 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.
NIHR Bioresource Rare Diseases, University of Cambridge RCV000851611 SCV000899363 uncertain significance Macrothrombocytopenia 2019-02-01 criteria provided, single submitter research
PreventionGenetics, part of Exact Sciences RCV004535741 SCV004113296 uncertain significance FLNA-related disorder 2023-02-06 criteria provided, single submitter clinical testing The FLNA c.6776T>C variant is predicted to result in the amino acid substitution p.Phe2259Ser. This variant has been reported in the hemizygous state in two individuals with platelet count disorders (Table S3 - Downes et al. 2019. PubMed ID: 31064749). This variant is reported in 0.0012% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/X-153580383-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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