Submissions for variant NM_001458.5(FLNC):c.1568T>C (p.Val523Ala)

gnomAD frequency: 0.00012  dbSNP: rs182845462

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482713	SCV000565016	uncertain significance	not provided	2021-04-23	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: 28356264)
Invitae	RCV001083373	SCV000771081	likely benign	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
CeGaT Center for Human Genetics Tuebingen	RCV000482713	SCV001155256	uncertain significance	not provided	2019-01-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402376	SCV002707058	likely benign	Cardiovascular phenotype	2023-04-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150235	SCV003837893	likely benign	Cardiomyopathy	2022-02-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993977	SCV004813855	likely benign	not specified	2024-02-05	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.1568T>C (p.Val523Ala) 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 0.00021 in 249522 control chromosomes (gnomAD). The observed variant frequency is approximately 27 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.1568T>C has been reported in the literature in individuals affected with Dilated Cardiomyopathy without strong evidence of causality (Lenarduzzi_2023, Pham_2023). These reports do not provide unequivocal conclusions about association of the variant with Dilated 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: 36788754, 37199186). ClinVar contains an entry for this variant (Variation ID: 418216). Based on the evidence outlined above, the variant was classified as likely benign.
Clinical Genetics, Academic Medical Center	RCV000482713	SCV001921697	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000482713	SCV001930783	uncertain significance	not provided		no assertion criteria provided	clinical testing