Submissions for variant NM_001458.5(FLNC):c.600C>T (p.Pro200=)

gnomAD frequency: 0.00013  dbSNP: rs202105410

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000513411	SCV000524408	likely benign	not provided	2021-05-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25214167)
CeGaT Center for Human Genetics Tuebingen	RCV000513411	SCV000609275	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	FLNC: BP4, BP7
Invitae	RCV001086125	SCV000651103	likely benign	Myofibrillar myopathy 5; Distal myopathy with posterior leg and anterior hand involvement; Hypertrophic cardiomyopathy 26; Dilated Cardiomyopathy, Dominant	2024-01-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002356563	SCV002656595	likely benign	Cardiovascular phenotype	2019-05-07	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	RCV003150210	SCV003837887	likely benign	Cardiomyopathy	2022-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001706629	SCV004038803	benign	not specified	2023-08-22	criteria provided, single submitter	clinical testing	Variant summary: FLNC c.600C>T (p.Pro200Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00022 in 245992 control chromosomes. The observed variant frequency is approximately 28-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.600C>T has been reported in the literature in an individual(s) affected with Cardiomyopathy without evidence of causality (Savarese_2014). This report does 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 publication has been ascertained in the context of this evaluation (PMID: 25214167). Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Clinical Genetics, Academic Medical Center	RCV001706629	SCV001920522	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000513411	SCV001931540	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000513411	SCV001959116	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000513411	SCV001971368	likely benign	not provided		no assertion criteria provided	clinical testing