ClinVar Miner

Submissions for variant NM_001458.4(FLNC):c.577G>A (p.Ala193Thr) (rs387906587)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000442836 SCV000521263 likely pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing The A193T variant in the FLNC gene has previously been reported to segregate with disease in at least one family with distal myopathy (Duff et al., 2011). Functional studies show that A193T increases the actin-binding activity of the filamin C protein compared to wild-type (Duff et al., 2011). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The A193T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. The A193T variant is a strong candidate for a pathogenic variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000600715 SCV000712399 uncertain significance not specified 2016-08-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Pathogenic. The p.Ala193Thr variant in FLNC has been reported in 1 individual with distal myopathy and segr egated with disease in 2 affected relatives (Duff 2011). This variant was absent from large population studies. In vitro functional studies provide some evidenc e that the p.Ala193Thr variant may impact protein function (Duff 2011). However, these types of assays may not accurately represent biological function. Computa tional prediction tools and conservation analysis suggest that the p.Ala193Thr v ariant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a path ogenic role, the clinical significance of the p.Ala193Thr variant is uncertain.
OMIM RCV000022429 SCV000043718 pathogenic Myopathy, distal, 4 2011-06-10 no assertion criteria provided literature only

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