Submissions for variant NM_001458.5(FLNC):c.1903C>T (p.Pro635Ser)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003060809	SCV003455815	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2023-10-10	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 635 of the FLNC protein (p.Pro635Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with FLNC-related conditions. ClinVar contains an entry for this variant (Variation ID: 2147268). 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.
Ambry Genetics	RCV004070428	SCV003633564	uncertain significance	Cardiovascular phenotype	2022-06-06	criteria provided, single submitter	clinical testing	The c.1903C>T (p.P635S) alteration is located in exon 12 (coding exon 12) of the FLNC gene. This alteration results from a C to T substitution at nucleotide position 1903, causing the proline (P) at amino acid position 635 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.