ClinVar Miner

Submissions for variant NM_001458.5(FLNC):c.3680C>T (p.Thr1227Ile)

gnomAD frequency: 0.00004  dbSNP: rs373573447
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000649179 SCV000771004 uncertain significance Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant 2023-10-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1227 of the FLNC protein (p.Thr1227Ile). This variant is present in population databases (rs373573447, gnomAD 0.006%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 30418145). ClinVar contains an entry for this variant (Variation ID: 539444). 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 FLNC 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 RCV001570028 SCV001794223 likely benign not provided 2020-04-08 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30418145)
Ambry Genetics RCV002343339 SCV002619173 uncertain significance Cardiovascular phenotype 2021-12-27 criteria provided, single submitter clinical testing The p.T1227I variant (also known as c.3680C>T), located in coding exon 21 of the FLNC gene, results from a C to T substitution at nucleotide position 3680. The threonine at codon 1227 is replaced by isoleucine, an amino acid with similar properties. This variant was reported in two individuals with hypertrophic cardiomyopathy (HCM); however, clinical details were limited (Ader F et al. Med Sci (Paris), 2018 Nov;34 Hors série n°2:39-41). This amino acid position is well 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.
Revvity Omics, Revvity RCV001570028 SCV003833184 uncertain significance not provided 2019-11-26 criteria provided, single submitter clinical testing

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