Submissions for variant NM_001458.5(FLNC):c.4055G>A (p.Arg1352His)

gnomAD frequency: 0.00004  dbSNP: rs746731567

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000799244	SCV000938898	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1352 of the FLNC protein (p.Arg1352His). This variant is present in population databases (rs746731567, gnomAD 0.009%), and has an allele count higher than expected for a pathogenic variant. 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: 645204). 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	RCV001592983	SCV001822226	uncertain significance	not provided	2020-12-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002477826	SCV002797558	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003479220	SCV004223584	likely benign	not specified	2023-11-09	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.4055G>A (p.Arg1352His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.3e-05 in 247064 control chromosomes (gnomAD). The observed variant frequency is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Cardiomyopathy phenotype (1.1e-05), strongly suggesting that the variant is benign. c.4055G>A has been reported in the literature in at least one individual affected with Hypertrophic cardiomyopathy (Mao_2020). These reports do not provide unequivocal conclusions about association of the variant with Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33557094, 32295012). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Revvity Omics, Revvity	RCV001592983	SCV004234824	uncertain significance	not provided	2023-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004027989	SCV004871157	uncertain significance	Cardiovascular phenotype	2023-03-06	criteria provided, single submitter	clinical testing	The c.4055G>A (p.R1352H) alteration is located in exon 23 (coding exon 23) of the FLNC gene. This alteration results from a G to A substitution at nucleotide position 4055, causing the arginine (R) at amino acid position 1352 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.