Submissions for variant NM_001458.5(FLNC):c.5071G>A (p.Asp1691Asn)

gnomAD frequency: 0.00006  dbSNP: rs777061037

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000691625	SCV000819411	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1691 of the FLNC protein (p.Asp1691Asn). This variant is present in population databases (rs777061037, gnomAD 0.02%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypertrophic cardiomyopathy, left ventricular non-compaction, and/or myofibrillar myopathy (PMID: 30539912, 30847666, 33890751). ClinVar contains an entry for this variant (Variation ID: 570701). 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.
CeGaT Center for Human Genetics Tuebingen	RCV002275117	SCV001155273	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	FLNC: PP3
Ambry Genetics	RCV002334294	SCV002643614	uncertain significance	Cardiovascular phenotype	2023-05-17	criteria provided, single submitter	clinical testing	The p.D1691N variant (also known as c.5071G>A), located in coding exon 30 of the FLNC gene, results from a G to A substitution at nucleotide position 5071. The aspartic acid at codon 1691 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported as de novo in a subject with skeletal myopathy (Zhang YT et al. Chin. Med. J., 2018 Dec;131:2986-2988). This variant has also been detected in a hypertrophic cardiomyopathy genetic testing case, and cases with noncompaction and/or dilated cardiomyopathy (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309; Shumkova M. Kardiol Pol. 2021 May;79(6):716-717; Ware SM. Am J Hum Genet. 2022 Feb;109(2):282-298). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002493176	SCV002800852	uncertain significance	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26	2021-10-26	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002275117	SCV003833072	uncertain significance	not provided	2021-06-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987667	SCV004803579	uncertain significance	not specified	2024-01-22	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.5071G>A (p.Asp1691Asn) results in a conservative amino acid change located in the Ig-like 15 region (Verdonschot_2020) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 249602 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in FLNC causing Dilated Cardiomyopathy phenotype (7.8e-06), strongly suggesting that the variant is benign. c.5071G>A has been reported in the literature in individuals affected with Limb-girdle muscular dystrophies, Filamin C Myopathy, Hypertrophic cardiomyopathy or Left ventricular noncompaction cardiomyopathy, including one de novo occurrence (Aurino_2008, Zhang_2018, van Lint_2019, Shumkova_2021). These data do not allow any conclusion about variant significance. 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: 19472918, 33890751, 32112656, 30539912, 30847666). ClinVar contains an entry for this variant (Variation ID: 570701). Based on the evidence outlined above, the variant was classified as uncertain significance.